Macrocyclization reactions and intermediates useful in the synthesis of analogs of halichondrin B

ABSTRACT

The invention provides methods for the synthesis of eribulin or a pharmaceutically acceptable salt thereof (e.g., eribulin mesylate) through a macrocyclization strategy. The macrocyclization strategy of the present invention involves subjecting a non-macrocyclic intermediate to a carbon-carbon bond-forming reaction (e.g., an olefination reaction (e.g., Horner-Wadsworth-Emmons olefination), Dieckmann reaction, catalytic Ring-Closing Olefin Metathesis, or Nozaki-Hiyama-Kishi reaction) to afford a macrocyclic intermediate. The invention also provides compounds useful as intermediates in the synthesis of eribulin or a pharmaceutically acceptable salt thereof and methods for preparing the same.

BACKGROUND

The invention relates to intermediates useful in the synthesis ofpharmaceutically active macrolide compounds and methods of synthesizingmacrolide compounds. Halichondrin B is a potent anticancer agentoriginally isolated from the marine sponge Halichondria okadai, andsubsequently found in Axinella sp., Phakellia carteri, and Lissodendoryxsp. A total synthesis of halichondrin B was published in 1992 (Aicher,T. D. et al., J. Am. Chem. Soc. 114:3162-3164). Eribulin mesylate (alsocalled Halaven®, E7389, and the mesylate salt of B1939), a nontaxanemicrotubule dynamics inhibitor, is a structurally simplified, syntheticanalogue of halichondrin B. Methods and intermediates for the synthesisof eribulin mesylate and other halichondrin B analogues are described inInternational Publication Nos. WO 2005/118565, WO 2009/046308, WO2009/064029, and WO 2009/124237; U.S. Pat. No. 6,214,865; Austad et al.,Synlett 24(3):333-337, 2013; Austad et al., Synlett. 24(3):327-332,2013; and Chase et al., Synlett 24(3):323-326, 2013; each of which ishereby incorporated by reference in its entirety. New methods for thesynthesis of halichondrin B analogs, in particular eribulin, aredesirable.

SUMMARY OF THE INVENTION

In general, the present invention provides methods for macrocyclizationof intermediates in the synthesis of eribulin or a pharmaceuticallyacceptable salt thereof (e.g., eribulin mesylate). The invention alsoprovides intermediates that can be employed in the macrocyclizationreactions described herein.

In a first aspect, the invention provides a method of preparing anintermediate in the synthesis of eribulin, the method includingperforming a macrocyclization reaction on a non-macrocyclicintermediate, the macrocyclization reaction producing the intermediatein the synthesis of eribulin by forming a C.15-C.16, C.2-C.3, C.3-C.4,C.19-C.20, C.0-C.1, or C.26-C.27 bond in the structure of eribulin.

In some embodiments of the first aspect, performing the macrocyclizationreaction can involve contacting the non-macrocyclic intermediate (e.g.,a compound of formula (IA)) with an olefin metathesis catalyst (e.g., aruthenium-carbene complex). The non-macrocyclic intermediate can be acompound of formula (IA) or a salt thereof:

-   -   where    -   R₁ is H or —CH₂X₁CH₂CH═CH₂, where X₁ is O, —C(R₉)₂—, or NP₅, and        where each R₉ is independently H or —COOR₁₀, P₅ is an        N-protecting group, and R₁₀ is C₁₋₆ alkyl;    -   (a1) R₂ is H or a hydroxyl protecting group, R₃ is C₁₋₆ alkyl        ether, and R₄ is H;    -   (a2) R₂ is H or a hydroxyl protecting group, and R₃ and R₄        combine to form a double bond;    -   or    -   (a3) R₂ and R₃ combine to form a bond, and R₄ is H;    -   (b1) R₅ is H or a hydroxyl protecting group, and R₆ and R₇        combine to form a double bond;    -   or    -   (b2) R₅ and R₆ combine to form a bond, and R₇ is H;    -   (c1) R₈ is H, and P₄ is H or a hydroxyl protecting group;    -   or    -   (c2) R₈ and P₄ combine to form a double bond;    -   each P₃ is independently H or a hydroxyl protecting group; and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form an aminal or                1,3-oxazolidin-2-one-5-yl; and    -   where the intermediate in the synthesis of eribulin can be a        compound of formula (IB) or a salt thereof:

In formula (IA) or (IB), each P₃ and P₄ can be independently a hydroxylprotecting group (e.g., a silyl). In formula (IA) or (IB), P₁ can be ahydroxyl protecting group (e.g., a silyl). In formula (IA) or (IB), Xcan be O. In formula (IA) or (IB), P₂ is a hydroxyl protecting group(e.g., a silyl). In formula (IA) or (IB), X can be N, and P₁ and P₂,together with the atoms to which each is attached, can combine to forman aminal. In formula (IA) or (IB), R₂ and R₃ can combine to form abond, and R₄ can be H. In formula (IA) or (IB), R₅ and R₆ can combine toform a bond, and R₇ can be H. In formula (IA) or (IB), R₈ can be H, andP₄ can be a hydroxyl protecting group (e.g., a silyl).

In particular embodiments of the first aspect, performing themacrocyclization reaction involves reacting the non-macrocyclicintermediate (e.g., a compound of formula (IIA)) with an organic base(e.g., an organic base having a pKa of 11±2 (e.g., DBU or trialkylamine(e.g., triethylamine))) and a Lewis acid (e.g., a salt of Li, Mg, or Zn(e.g., lithium chloride or zinc trifluoromethanesulfonate)). Inparticular, the method can involve performing a Horner-Wadsworth-Emmonsreaction on the compound of formula (IIA) to afford the compound offormula (IIB). The non-macrocyclic intermediate can be a compound offormula (IIA) or a salt thereof:

-   -   where    -   each R is independently optionally substituted alkyl or        optionally substituted aryl;    -   (i) R₁ is H or a hydroxyl protecting group, and R₂ and R₃        combine to form a double bond;    -   or    -   (ii) R₁ and R₂ combine to form a bond, and R₃ is H;    -   each P₃ is independently H or a hydroxyl protecting group, and        X₂ is oxo; or both P₃ groups and X₂, together with the atoms to        which each is attached, combine to form ketal;    -   P₄ is H or a hydroxyl protecting group; and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form an aminal or                1,3-oxazolidin-2-one-5-yl; and    -   where the intermediate in the synthesis of eribulin can be a        compound of formula (IIB) or a salt thereof:

In formula (IIA), each R can be optionally substituted alkyl. In formula(IIA) or (IIB), P₁ can be a hydroxyl protecting group (e.g., a silyl).In formula (IIA) or (IIB), P₂ can be a hydroxyl protecting group (e.g.,a silyl). In formula (IIA) or (IIB), both P₃ groups and X₂, togetherwith the atoms to which each is attached, can combine to form ketal. Informula (IIA) or (IIB), R₁ and R₂ can form a bond, and R₃ can be H. Informula (IIA) or (IIB), P₄ can be a hydroxyl protecting group (e.g., asilyl).

In some embodiments of the first aspect, performing the macrocyclizationreaction involves contacting the non-macrocyclic intermediate (e.g., acompound of formula (IIIA)) with an olefin metathesis catalyst (e.g., aruthenium-carbene complex). The non-macrocyclic intermediate can be acompound of formula (IIIA) or a salt thereof:

-   -   where    -   (i) R₁ is H or a hydroxyl protecting group, and R₂ and R₃        combine to form a double bond;    -   or    -   (ii) R₁ and R₂ combine to form a bond, and R₃ is H;    -   X₃ is oxo, or X₃ combine with the carbon atom to which it is        attached to form a ketal, a thioketal, or —(CH(OP₅))—, where P₅        is H or a hydroxyl protecting group;    -   each P₃ is independently H or a hydroxyl protecting group, and        X₂ is oxo; or both P₃ groups and X₂, together with the atoms to        which each is attached, combine to form ketal;    -   P₄ is H or a hydroxyl protecting group; and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form an aminal or                1,3-oxazolidin-2-one-5-yl; and    -   where the intermediate in the synthesis of eribulin can be a        compound of formula (IIIB) or a salt thereof:

In formula (IIIA) or (IIIB), P₄ can be a hydroxyl protecting group(e.g., a silyl). In formula (IIIA) or (IIIB), both P₃ groups and X₂,together with the atoms to which each is attached, can combine to formketal. In formula (IIIA) or (IIIB), R₁ and R₂ can form a bond, and R₃can be H. In formula (IIIA) or (IIIB), X₃ can combine with the carbonatom to which it is attached to form —(CH(OP₅))—. In particular, informula (IIIA) or (IIIB), P₅ can be H. In formula (IIIA) or (IIIB), P₁can be a hydroxyl protecting group (e.g., silyl). In formula (IIIA) or(IIIB), P₂ can be a hydroxyl protecting group.

In certain embodiments of the first aspect, performing themacrocyclization reaction includes contacting the non-macrocyclicintermediate (e.g., a compound of formula (IVA)) with a Cr(II) salt anda Ni(II) salt. In particular, the method can involve subjecting acompound of formula (IVA) to Nozaki-Hiyama-Kishi reaction conditions.The non-macrocyclic intermediate can be a compound of formula (IVA) or asalt thereof:

-   -   where    -   Y is iodide, bromide, or trifluoromethanesulfonate;    -   a can designate R stereogenic center, and Z is a sulfonate,        chloride, bromide, or iodide; or a can designate S stereogenic        center, and Z is OR₁, where R₁ is a hydroxyl protecting group;    -   (i) R₂ is H or a hydroxyl protecting group, and R₃ and R₄        combine to form a double bond;    -   or    -   (ii) R₂ and R₃ combine to form a bond, and R₄ is H;    -   each P₃ is independently H or a hydroxyl protecting group, and        X₂ is oxo; or both P₃ groups and X₂, together with the atoms to        which each is attached, combine to form ketal; and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form an aminal or                1,3-oxazolidin-2-one-5-yl; and    -   where the intermediate in the synthesis of eribulin can be a        compound of formula (IVB) or a salt thereof:

-   -   where        -   a designates R stereogenic center, b designates S            stereogenic center, and Z is a sulfonate, chloride, bromide,            or iodide;        -   or        -   a designates S stereogenic center, b designates R            stereogenic center, and Z is OR₁, where R₁ is a hydroxyl            protecting group.

In formula (IVA) or (IVB), Y can be bromide. In formula (IVA) or (IVB),R₂ and R₃ can combine to form a bond, and R₄ can be H. In formula (IVA)or (IVB), both P₃ groups and X₂, together with the atoms to which eachis attached, can combine to form ketal. In formula (IVA) or (IVB), P₁can be a hydroxyl protecting group (e.g., a silyl). In formula (IVA) or(IVB), P₂ can be a hydroxyl protecting group (e.g., a silyl). In formula(IVA) or (IVB), Z can be a sulfonate. In formula (IVA) or (IVB), Z canbe OR₁, where R₁ can be a hydroxyl protecting group (e.g., Z can be anester, carbonate, or carbamate (e.g., Z can be an ester)).

In some embodiments of the first aspect, performing the macrocyclizationreaction involves contacting the non-macrocyclic intermediate (e.g., acompound of formula (VA)) with a base (e.g., a tertiary C₄₋₆ alkoxide(e.g., an alkali tertiary C₄₋₆ alkoxide)). In particular, the method caninvolve subjecting a compound of formula (VA) to the Dieckmann reactionconditions. The non-macrocyclic intermediate can be a compound offormula (VA) or a salt thereof:

-   -   where    -   Y is SO₂R₁ or COOR₁, where, when Y is SO₂R₁, R₁ is optionally        substituted aryl or optionally substituted non-enolizable alkyl,        and when Y is COOR₁, R₁ is optionally substituted alkyl,        optionally substituted aryl, or optionally substituted        arylalkyl;    -   each P₃ is independently H or a hydroxyl protecting group, and        X₂ is oxo, or both P₃ groups and X₂, together with the atoms to        which each is attached, combine to form ketal;    -   R₂ is optionally substituted alkyl, optionally substituted        arylalkyl, or optionally substituted aryl; and    -   X is O, and        -   each of P₁ and P₂ is independently a hydroxyl protecting            group,        -   or        -   P₁ and P₂, together with the atoms to which each is            attached, combine to form a cyclic protected diol;    -   or    -   X is N, and        -   P₁ is H or a hydroxyl protecting group, and X and P₂ combine            to form optionally masked amino;        -   or        -   P₁ and P₂, together with the atoms to which each is            attached, combine to form an aminal or            1,3-oxazolidin-2-one-5-yl; and    -   where the intermediate in the synthesis of eribulin can be a        compound of formula (VB) or a salt thereof:

-   -   where    -   (i) R₃ is H, R₄ is optionally substituted C₁₋₆ alkyl ether, and        R₅ is H;    -   (ii) R₅ is H, and R₃ and R₄ combine to form a double bond;    -   or    -   (iii) R₃ is H, and R₄ and R₅ combine to form a bond.

In formula (VA) or (VB), Y can be SO₂R₁ (e.g., R₁ can be optionallysubstituted aryl). In formula (VA) or (VB), both P₃ groups and X₂,together with the atoms to which each is attached, can combine to formketal. In formula (VA) or (VB), R₂ can be optionally substituted alkyl(e.g., unsubstituted C₁₋₆ alkyl). In formula (VA) or (VB), R₃ can be H,and R₄ and R₅ can combine to form a bond.

In other embodiments of the first aspect, performing themacrocyclization reaction includes contacting the non-macrocyclicintermediate (e.g., a compound of formula (VIA)) with a Cr(II) salt anda Ni(II) salt. In particular, the method can involve subjecting acompound of formula (VIA) to Nozaki-Hiyama-Kishi reaction conditions.The non-macrocyclic intermediate can be a compound of formula (VIA) or asalt thereof:

-   -   where    -   Y is iodide, bromide, or trifluoromethanesulfonate;    -   (a1) R₃ is H or a hydroxyl protecting group, R₄ and R₅ combine        to form a double bond, each P₃ is independently H or a hydroxyl        protecting group, and X₂, together with the carbon to which it        is attached, form a carbonyl or —(CH(OR₆))—, where R₆ is H or a        hydroxyl protecting group;    -   or    -   (a2) R₃ and R₄ combine to form a bond, R₅ is H, and        -   each P₃ is independently H or a hydroxyl protecting group,            and X₂, together with the carbon to which it is attached,            form a carbonyl or —(CH(OR₆))—;        -   or        -   both P₃ groups and X₂, together with the atoms to which each            is attached, combine to form ketal;    -   (b1) Z is chloride, bromide, or iodide, and R₁ and R₂ combine to        form a bond;    -   or    -   (b2) Z and R₂ combine to form a double bond, and R₁ is a        hydroxyl protecting group;    -   and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group, or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form an aminal or                1,3-oxazolidin-2-one-5-yl; and    -   where the intermediate in the synthesis of eribulin is a        compound of formula (VIB) or a salt thereof:

-   -   where P₄ is H or a hydroxyl protecting group.

In formula (VIA), Z can be iodide, and R₁ and R₂ can combine to form abond. In formula (VIA), Y can be trifluoromethanesulfonate. In formula(VIA) or (VIB), R₁ can be H, or O and R₁ can combine to form asulfonate. In formula (VIA) or (VIB), P₁ can be a hydroxyl protectinggroup (e.g., a silyl). In formula (VIA) or (VIB), P₂ can be a hydroxylprotecting group (e.g., a silyl). In formula (VIA) or (VIB), R₃ can be Hor a hydroxyl protecting group, R₄ and R₅ can combine to form a doublebond, each P₃ can be independently H or a hydroxyl protecting group, andX₂, together with the carbon to which it is attached, can form acarbonyl or —(CH(OR₆))—, where R₆ can be H or a hydroxyl protectinggroup. In formula (VIA) or (VIB), R₃ can be a hydroxyl protecting group(e.g., a silyl), R₄ and R₅ can combine to form a double bond, each P₃can be independently a hydroxyl protecting group, and X₂, together withthe carbon to which it is attached, can form a carbonyl or —(CH(OR₆))—,where R₆ can be H or a hydroxyl protecting group (e.g., O can combinewith R₆ to form an ester). In formula (VIB), P₄ can be a hydroxylprotecting group (e.g., O and P₄ can combine to form an ester).

Preparation of the Compound of Formula (VIB) from the Compound ofFormula (VIA) can Further Involve

In a second aspect, the invention provides a method of preparing:

In some embodiments of the second aspect, the method involves:

-   -   (A) producing a compound of formula (IB) from a compound of        formula (IA), the compound of formula (IA) having the following        structure:

-   -   where    -   R₁ is H or —CH₂X₁CH₂CH═CH₂, where X₁ is O, —C(R₉)₂—, or NP₅, and        where each R₉ is independently H or —COOR₁₀, P₅ is an        N-protecting group, and R₁₀ is C₁₋₆ alkyl;    -   (a1) R₂ is H or a hydroxyl protecting group, R₃ is C₁₋₆ alkyl        ether, and R₄ is H;    -   (a2) R₂ is H or a hydroxyl protecting group, and R₃ and R₄        combine to form a double bond;    -   or    -   (a3) R₂ and R₃ combine to form a bond, and R₄ is H;    -   (b1) R₅ is H or a hydroxyl protecting group, and R₆ and R₇        combine to form a double bond;    -   or    -   (b2) R₅ and R₆ combine to form a bond, and R₇ is H;    -   (c1) R₈ is H, and P₄ is H or a hydroxyl protecting group;    -   or    -   (c2) R₈ and P₄ combine to form a double bond;    -   each P₃ is independently H or a hydroxyl protecting group; and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form an aminal or                1,3-oxazolidin-2-one-5-yl;    -   the compound of formula (IB) having the following structure:

-   -   where each variable is as defined for formula (IA).

The method can involve (B) producing a compound of formula (IC) from thecompound of formula (IB), the compound of formula (IC) having thefollowing structure:

-   -   where each variable can be as defined for formula (IB).

The method can involve (C) producing a compound of formula (ID) from thecompound of formula (IC), the compound of formula (ID) having thefollowing structure:

-   -   where each P₃ is independently H or a hydroxyl protecting group,        and X₂ is oxo; or both P₃ groups and X₂, together with the atoms        to which each is attached, combine to form ketal; and each of        the remaining variables is as defined for formula (IC).

The method can further involve (D) producing eribulin or eribulinmesylate from the compound of formula (ID).

In formula (IA) or (IB), P₄ can be a hydroxyl protecting group (e.g., asilyl). In formula (IA) or (IB), R₂ and R₃ can combine to form a bond,and R₄ can be H. In formula (IA) or (IB), R₅ and R₆ can combine to forma bond, and R₇ can be H. In formula (IA) or (IB), R₈ can be H, and P₄can be a hydroxyl protecting group (e.g., a silyl).

In formula (IA) or (IB), each P₃ can be independently a hydroxylprotecting group (e.g., a silyl). In formula (IC), P₃ can be H or ahydroxyl protecting group (e.g., a silyl).

In formula (IA), (IB), (IC), or (ID), P₁ can be a hydroxyl protectinggroup (e.g., a silyl). In formula (IA) or (IB), X can be O. In formula(IA), (IB), (IC), or (ID), P₂ is a hydroxyl protecting group (e.g., asilyl). In formula (IA), (IB), (IC), or (ID), X can be N, and P₁ and P₂,together with the atoms to which each is attached, can combine to forman aminal.

The method can further involve oxidizing the compound of formula (IB)(e.g., when R₈ is H) with an olefin metathesis catalyst, e.g., byreacting with an oxidizing agent capable of oxidizing an alcohol to acarbonyl group (e.g., Dess-Martin periodinane). If, P₄ is a hydroxylprotecting group (e.g., a silyl) in the compound of formula (IB), thiscompound can be reacted with a hydroxyl protecting group removing agentprior to oxidizing the compound of formula (IB).

Producing the compound of formula (IB) from the compound of formula (IA)can involve reacting the compound of formula (IA) with an olefinmetathesis catalyst.

Producing the compound of formula (IC) can include oxidizing thecompound of formula (IB), where, in the compound of formula (IB), R₈ isH, and P₄ is H, e.g., by reacting the compound of formula (IB) with anoxidizing agent capable of oxidizing an alcohol to a carbonyl group(e.g., Dess-Martin periodinane).

Producing the compound of formula (ID) can include reacting the compoundof formula (IC) with a 1,4-reducing agent. The compound of formula (ID),in which each P₃ is independently a hydroxyl protecting group, can bereacted with a hydroxyl protecting group removing agent to afford tejcompound of formula (ID), in which each P₃ is H or both P₃ groups andX₂, together with the atoms to which each is attached, combine to formketal.

In formula (ID), both P₃ groups and X₂, together with the atoms to whicheach is attached, can combine to form ketal. In formula (ID), P₁ can beH. In formula (ID), X can be O, and P₂ can be H. Producing eribulin oreribulin mesylate from the compound of formula (ID) can includeaminating the compound of formula (ID).

In formula (ID), X and P₂ can combine to form a masked amino. Producingeribulin or eribulin mesylate from the compound of formula (ID) caninvolve reacting the compound of formula (ID) with an amino unmaskingagent.

Eribulin mesylate can be produced by salifying eribulin withmethanesulfonic acid.

In certain embodiments of the second aspect, the method involves:

-   -   (A) producing a compound of formula (IIB) from a compound of        formula (IIA) or a salt thereof:

-   -   where    -   each R is independently optionally substituted alkyl or        optionally substituted aryl;    -   (i) R₁ is H or a hydroxyl protecting group, and R₂ and R₃        combine to form a double bond;    -   or    -   (ii) R₁ and R₂ combine to form a bond, and R₃ is H;    -   each P₃ is independently H or a hydroxyl protecting group, and        X₂ is oxo; or both P₃ groups and X₂, together with the atoms to        which each is attached, combine to form ketal;    -   P₄ is H or a hydroxyl protecting group; and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form an aminal or                1,3-oxazolidin-2-one-5-yl; and    -   the compound of formula (IIB) having the following structure:

-   -   (B) producing a compound of formula (ID) from the compound of        formula (IIB), the compound of formula (ID) having the following        structure:

-   -   and    -   (C) producing eribulin or eribulin mesylate from the compound of        formula (ID).

In formula (IIA), each R can be optionally substituted alkyl. In formula(IIA) or (IIB), P₁ can be a hydroxyl protecting group (e.g., a silyl).In formula (IIA) or (IIB), P₂ can be a hydroxyl protecting group (e.g.,a silyl). In formula (IIA) or (IIB), R₁ and R₂ can form a bond, and R₃can be H. In formula (IIA) or (IIB), P₄ can be a hydroxyl protectinggroup (e.g., a silyl). In formula (IIA), (IIB), or (ID), both P₃ groupsand X₂, together with the atoms to which each is attached, can combineto form ketal.

Producing the compound of formula (IIB) can involve reacting thecompound of formula (IIA) with an organic base (e.g., an organic basehaving a pKa of 11±2 (e.g., DBU or trialkylamine (e.g., triethylamine)))and a Lewis acid (e.g., a salt of Li, Mg, or Zn (e.g., lithium chlorideor zinc trifluoromethanesulfonate)).

Producing the compound of formula (ID) can involve reacting the compoundof formula (IIB) with a hydroxyl protecting group removing agent.

In formula (ID), both P₃ groups and X₂, together with the atoms to whicheach is attached, can combine to form ketal. In formula (ID), P₁ can beH. In formula (ID), X can be O, and P₂ can be H. Producing eribulin oreribulin mesylate from the compound of formula (ID) can includeaminating the compound of formula (ID).

In formula (ID), X and P₂ can combine to form a masked amino. Producingeribulin or eribulin mesylate from the compound of formula (ID) caninvolve reacting the compound of formula (ID) with an amino unmaskingagent.

Eribulin mesylate can be produced by salifying eribulin withmethanesulfonic acid.

In certain embodiments of the second aspect, the method involves:

-   -   (A) producing a compound of formula (IIIB) from the compound of        formula (IIIA), the compound of formula (IIIA) having the        following structure:

-   -   where    -   (i) R₁ is H or a hydroxyl protecting group, and R₂ and R₃        combine to form a double bond;        -   or    -   (ii) R₁ and R₂ combine to form a bond, and R₃ is H;    -   X₃ is oxo, or X₃ combines with the carbon atom to which it is        attached to form a ketal, a thioketal, or —(CH(OP₅))—, where P₅        is H or a hydroxyl protecting group; each P₃ is independently H        or a hydroxyl protecting group, and X₂ is oxo; or both P₃ groups        and X₂, together with the atoms to which each is attached,        combine to form ketal;    -   P₄ is H or a hydroxyl protecting group; and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form an aminal or                1,3-oxazolidin-2-one-5-yl;    -   the compound of formula (IIIB) having the following structure:

-   -   (B) producing a compound of formula (ID) from the compound of        formula (IIIB), the compound of formula (ID) having the        following structure:

-   -   and    -   (C) producing eribulin or eribulin mesylate from the compound of        formula (ID).

In formula (IIIA) or (IIIB), P₄ can be a hydroxyl protecting group(e.g., a silyl). In formula (IIIA) or (IIIB), R₁ and R₂ can form a bond,and R₃ can be H. In formula (IIIA) or (IIIB), X₃ can combine with thecarbon atom to which it is attached to form —(CH(OP₅))—. In particular,in formula (IIIA) or (IIIB), P₅ can be H. In formula (IIIA) or (IIIB),P₁ can be a hydroxyl protecting group (e.g., silyl). In formula (IIIA)or (IIIB), P₂ can be a hydroxyl protecting group. In formula (IIIA),(IIIB), or (ID), both P₃ groups and X₂, together with the atoms to whicheach is attached, can combine to form ketal.

Producing the compound of formula (IIIB) can involve reacting thecompound of formula (IIIA) with an olefin metathesis catalyst.

Producing the compound of formula (ID) can involve oxidizing (e.g., byreacting with an oxidizing agent capable of oxidizing an alcohol to acarbonyl group) the compound of formula (IIIB), where, in the compoundof formula (IIIB), X₃, together with the carbon to which it is attached,forms —(CH(OP₅))—, where P₅ is H.

Producing the compound of formula (ID) can also involve reacting thecompound of formula (IIIB), where, in the compound of formula (IIIB), P₄is a hydroxyl protecting group, and R₄ and R₅ combine to form a doublebond, with a hydroxyl protecting group removing agent.

In formula (ID), both P₃ groups and X₂, together with the atoms to whicheach is attached, can combine to form ketal. In formula (ID), P₁ can beH. In formula (ID), X can be O, and P₂ can be H. Producing eribulin oreribulin mesylate from the compound of formula (ID) can includeaminating the compound of formula (ID).

In formula (ID), X and P₂ can combine to form a masked amino. Producingeribulin or eribulin mesylate from the compound of formula (ID) caninvolve reacting the compound of formula (ID) with an amino unmaskingagent.

Eribulin mesylate can be produced by salifying eribulin withmethanesulfonic acid.

In certain embodiments of the second aspect, the method includes:

-   -   (A) producing a compound of formula (IVB) from a compound of        formula (IVA), the compound of formula (IVA) having the        following structure:

-   -   where    -   Y is iodide, bromide, or trifluoromethanesulfonate;    -   a designates R stereogenic center, and Z is a sulfonate,        chloride, bromide, or iodide; or a designates S stereogenic        center, and Z is OR₁, where R₁ is a hydroxyl protecting group;    -   (i) R₂ is H or a hydroxyl protecting group, and R₃ and R₄        combine to form a double bond;    -   or    -   (ii) R₂ and R₃ combine to form a bond, and R₄ is H;    -   each P₃ is independently H or a hydroxyl protecting group, and        X₂ is oxo; or both P₃ groups and X₂, together with the atoms to        which each is attached, combine to form ketal; and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or        -   P₁ and P₂, together with the atoms to which each is            attached, combine to form an aminal or            1,3-oxazolidin-2-one-5-yl;    -   the compound of formula (IVB) having the following structure:

-   -   where        -   a designates R stereogenic center, b designates S            stereogenic center, and Z is a sulfonate, chloride, bromide,            or iodide;        -   or        -   a designates S stereogenic center, b designates R            stereogenic center, and Z is OR₁, where R₁ is a hydroxyl            protecting group;    -   (B) producing a compound of formula (ID) from the compound of        formula (IVB), the compound of formula (ID) having the following        structure:

-   -   and    -   (C) producing eribulin or eribulin mesylate from the compound of        formula (ID).

In formula (IVA) or (IVB), Y can be bromide. In formula (IVA) or (IVB),R₂ and R₃ can combine to form a bond, and R₄ can be H. In formula (IVA)or (IVB), P₁ can be a hydroxyl protecting group (e.g., a silyl). Informula (IVA) or (IVB), P₂ can be a hydroxyl protecting group (e.g., asilyl). In formula (IVA) or (IVB), Z can be a sulfonate. In formula(IVA) or (IVB), Z can be OR₁, where R₁ can be a hydroxyl protectinggroup (e.g., Z can be an ester, carbonate, or carbamate (e.g., Z can bean ester)). In formula (IVA), (IVB), or (ID), both P₃ groups and X₂,together with the atoms to which each is attached, can combine to formketal.

Producing the compound of formula (IVB) can involve reacting thecompound of formula (IVA) with a Cr(II) salt and a Ni(II) salt.Producing the compound of formula (IVB) can involve subjecting thecompound of formula (IVA) to Nozaki-Hiyama-Kishi reaction conditions.

Producing the compound of formula (ID) can involve the step ofnucleophilic ring-closing of the compound of formula (IVB).

In formula (ID), both P₃ groups and X₂, together with the atoms to whicheach is attached, can combine to form ketal. In formula (ID), P₁ can beH. In formula (ID), X can be O, and P₂ can be H. Producing eribulin oreribulin mesylate from the compound of formula (ID) can includeaminating the compound of formula (ID).

In formula (ID), X and P₂ can combine to form a masked amino. Producingeribulin or eribulin mesylate from the compound of formula (ID) caninvolve reacting the compound of formula (ID) with an amino unmaskingagent.

Eribulin mesylate can be produced by salifying eribulin withmethanesulfonic acid.

In particular embodiments of the second aspect, the method includes:

-   -   (A) producing a compound of formula (VB) from a compound of        formula (VA):

-   -   where    -   Y is SO₂R₁ or COOR₁, where, when Y is SO₂R₁, R₁ is optionally        substituted aryl or optionally substituted non-enolizable alkyl,        and when Y is COOR₁, R₁ is optionally substituted alkyl,        optionally substituted aryl, or optionally substituted        arylalkyl;    -   each P₃ is independently H or a hydroxyl protecting group, and        X₂ is oxo, or both P₃ groups and X₂, together with the atoms to        which each is attached, combine to form ketal;    -   R₂ is optionally substituted alkyl, optionally substituted        arylalkyl, or optionally substituted aryl; and    -   X is O, and        -   each of P₁ and P₂ is independently a hydroxyl protecting            group,        -   or        -   P₁ and P₂, together with the atoms to which is each is            attached, combine to form a cyclic protected diol;    -   or    -   X is N, and        -   P₁ is H or a hydroxyl protecting group, and X and P₂ combine            to form optionally masked amino;        -   or        -   P₁ and P₂, together with the atoms to which each is            attached, combine to form an aminal or            1,3-oxazolidin-2-one-5-yl;    -   the compound of formula (VB) having the following structure:

-   -   where    -   (i) R₃ is H, R₄ is ether, and R₅ is H;    -   (ii) R₅ is H, and R₃ and R₄, together with the bond connecting        the atoms to which each is attached, combine to form a double        bond;    -   or    -   (iii) R₃ is H, and R₄ and R₅ combine to form a bond;    -   (B) producing a compound of formula (ID) from the compound of        formula (VB), the compound of formula (ID) having the following        structure:

-   -   and    -   (C) producing eribulin or eribulin mesylate from the compound of        formula (ID).

In formula (VA) or (VB), Y can be SO₂R₁ (e.g., R₁ can be optionallysubstituted aryl). In formula (VA) or (VB), R₂ can be optionallysubstituted alkyl (e.g., unsubstituted C₁₋₆ alkyl). In formula (VB), R₃can be H, and R₄ and R₅ can combine to form a bond. In formula (VA),(VB), or (ID), both P₃ groups and X₂, together with the atoms to whicheach is attached, can combine to form ketal.

Producing the compound of formula (VB) can involve reacting the compoundof formula (VA) with a strong base (e.g., a tertiary C₄₋₆ alkoxide).

Producing the compound of formula (ID) can involve reacting the compoundof formula (VB), in which Y is SO₂R₁, and R₁ is optionally substitutedaryl, with an electron-transferring reducing agent (e.g., SmI₂, Mg(0),or Cr(III) with Mn(0)).

In formula (ID), both P₃ groups and X₂, together with the atoms to whicheach is attached, can combine to form ketal. In formula (ID), P₁ can beH. In formula (ID), X can be O, and P₂ can be H. Producing eribulin oreribulin mesylate from the compound of formula (ID) can includeaminating the compound of formula (ID).

In formula (ID), X and P₂ can combine to form a masked amino. Producingeribulin or eribulin mesylate from the compound of formula (ID) caninvolve reacting the compound of formula (ID) with an amino unmaskingagent.

Eribulin mesylate can be produced by salifying eribulin withmethanesulfonic acid.

In other embodiments of the second aspect, the method includes:

-   -   (A) producing a compound of formula (VIB) from a compound of        formula (VIA), the compound of formula (VIA) having the        following structure:

-   -   where    -   Y is iodide, bromide, or trifluoromethanesulfonate;    -   (a1) R₃ is H or a hydroxyl protecting group, R₄ and R₅ combine        to form a double bond, each P₃ is independently H or a hydroxyl        protecting group, and X₂, together with the carbon to which it        is attached, forms a carbonyl or —(CH(OR₆))—, where R₆ is H or a        hydroxyl protecting group;    -   or    -   (a2) R₃ and R₄ combine to form a bond, R₅ is H, and        -   each P₃ is independently H or a hydroxyl protecting group,            and X₂, together with the carbon to which it is attached,            forms a carbonyl or —(CH(OR₆))—;        -   or        -   both P₃ groups and X₂, together with the atoms to which each            is attached, combine to form ketal;    -   (b1) Z is chloride, bromide, or iodide, and R₁ and R₂ combine to        form a bond;    -   or    -   (b2) Z and R₂ combine to form a double bond, and R₁ is a        hydroxyl protecting group;    -   and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group, or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form an aminal or                1,3-oxazolidin-2-one-5-yl; and    -   the compound of formula (VIB) having the following structure:

-   -   where P₄ is H or a hydroxyl protecting group;    -   (B) producing a compound of formula (VIC) from the compound of        formula (VIB), the compound of formula (VIC) having the        following structure:

-   -   (C) producing a compound of formula (ID) from the compound of        formula (VIC), the compound of formula (ID) having the following        structure:

-   -   and    -   (D) producing eribulin or eribulin mesylate from the compound of        formula (ID).

Producing the compound of formula (VIB) can include reacting thecompound of formula (VIA) with a Cr(II) salt and a Ni(II) salt.

Producing the compound of formula (ID) can include reacting the compoundof formula (VIB) with a hydroxyl protecting group removing agent.

In formula (ID), both P₃ groups and X₂, together with the atoms to whicheach is attached, can combine to form ketal. In formula (ID), P₁ can beH. In formula (ID), X can be O, and P₂ can be H. Producing eribulin oreribulin mesylate from the compound of formula (ID) can includeaminating the compound of formula (ID).

In formula (ID), X and P₂ can combine to form a masked amino. Producingeribulin or eribulin mesylate from the compound of formula (ID) caninvolve reacting the compound of formula (ID) with an amino unmaskingagent.

Eribulin mesylate can be produced by salifying eribulin withmethanesulfonic acid.

In a third aspect, the invention provides a method of preparing anintermediate in the synthesis of eribulin, the method includingperforming a Prins reaction by contacting a compound of formula (VIIA)with a compound of formula (VIIB) and R₃OH,

-   -   where R₃ can be an optionally substituted acyl;    -   where the compound of formula (VIIA) can have the following        structure:

-   -   where    -   Y₁ is SO₂R₁ or COOR₁, and R₁ is optionally substituted alkyl,        optionally substituted aryl, or optionally substituted        arylalkyl;    -   X₁ is O, or X₁, together with the carbon to which it is        attached, forms a cyclic acetal; and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form an aminal or                1,3-oxazolidin-2-one-5-yl;    -   where the compound of formula (VIIB) can have the following        structure:

-   -   -   where        -   R₂ is —CH₂—OP₃,

-   -   -   -   where P₃ is H or a hydroxyl protecting group; each P₄ is                independently a hydroxyl protecting group, or both P₄                groups, together with the atoms to which each is                attached, combine to form a cyclic protected diol; and                R₄ is is H or —CH₂X₂CH₂CH═CH₂, where X₂ is O, —CH₂—, or                NP₅, where P₅ is sulfonyl;

    -   and where the intermediate is a compound of formula (VIIC):

Performing a Prins reaction can involve reacting the compound of formula(VIIA) with a Lewis acid (e.g., boron trifluoride or a solvate thereof).

In a fourth aspect, the invention provides a method of preparing anintermediate in the synthesis of eribulin, the method can involve:

-   -   (A) cleaving the double bond in a compound of formula (VIIIA) to        afford a compound of formula (VIIIB), the compound of formula        (VIIIA) having the structure:

-   -   where        -   X₁ can be oxo, or X₁, together with the carbon atom to which            it can be attached, forms a ketal or —(CH(OP₃))—, where P₃            can be H or a hydroxyl protecting group;        -   R₁ can be H or —CH₂OP₄;        -   each of P₁, P₂, and P₄ can be independently a hydroxyl            protecting group, or        -   P₁ and P₄, together with the atoms to which each can be            attached, can combine to form a cyclic protected diol; and    -   the compound of formula (VIIIB) having the structure:

-   -   (B) reacting the compound of formula (VIIIB) with a compound of        formula (VIIIB-a) to afford a compound of formula (VIIIC):

-   -   where R₂ can be H or —CH₂CH₂OP₅, and P₅ can be a hydroxyl        protecting group;    -   and the compound of formula (VIIIB-a) has the following        structure:

-   -   (C) reacting the compound of formula (VIIIC) with a dehydrating        agent to afford a compound of formula (VIIID):

-   -   (D) reacting the compound of formula (VIIID) with a        dihydroxylating agent to afford a compound of formula (VIIIE):

-   -   (E) preparing a compound of formula (VIIIF) through a reaction        sequence including reacting the compound of formula (VIIIE) with        N-bromosuccinimide to afford a first intermediate, reacting the        first intermediate with an acylating agent (e.g., a carboxylic        acid anhydride) to afford a second intermediate, and (a), when        R₂ can be —CH₂CH₂OP₅, contacting the second intermediate with a        reducing agent, or (b), when R₂ can be H, allylating the second        intermediate compound of formula (VIIIF):

-   -   where Z can be an ester or —OP₇, where P₇ can be H or a hydroxyl        protecting group, and R₃ can be —CH₂CH₂OP₅ or —CH₂CH═CH₂;    -   (F) reacting the compound of formula (VIIIF) with a 1,4-reducing        agent to afford a compound of formula (VIIIG):

-   -    and    -   (G) forming a compound of formula (VIIIH) through a reaction        sequence including reacting the compound of formula (VIIIG) with        a Brønsted acid and Y—H, where Y can be optionally substituted        C₁₋₆ alkyl, the compound of formula (VIIIH) having the following        structure:

-   -   where Y can be optionally substituted C₁₋₆ alkyl ether; R₂ can        be —CH₂CH₂OP₅; X₂ can be oxo, or X₂, together with the carbon to        which it can be attached, forms a ketal or —(CH(OP₆))—, where P₆        can be a hydroxyl protecting group.

In some embodiments of the fourth aspect, the method further includes:

-   -   (H) replacing P₂ in the compound of formula (VIIIH) with        —Si(R₄)₂H to afford a compound of formula (VIIIJ):

-   -   where each R₄ is independently optionally substituted alkyl,        optionally substituted aryl, or optionally substituted        arylalkyl;    -   (I) reacting the compound of formula (VIIIJ) with a Lewis acid        to afford a compound of formula (VIIIK):

-   -   where Y₁ is fluoro, chloro, or bromo; and    -   (J) reacting the compound of formula (VIIIK) with a hydroxyl        protecting group removing agent and then reacting with a        hydroxyl protecting agent to afford a compound of formula        (VIIIL):

-   -   where P₂ is a hydroxyl protecting group.

In a fifth aspect, the invention provides compounds of formulas (IA),(IB), (IC), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (IVE), (VA),(VB), (VIA), (VIB), (VIIB), and (VIIC). The invention also providescompounds of formulas (VIIIC), (VIIID), (VIIIE), (VIIIF), (VIIIG),(VIIIH), (VIIIJ), (VIIIK), and (VIIIL).

A compound of the fifth aspect can be a compound of formula (IA) or(IB):

-   -   or a salt thereof,    -   where    -   R₁ is H or —CH₂X₁CH₂CH═CH₂, where X₁ is O, —C(R₉)₂—, or NP₅, and        where each R₉ is independently H or —COOR₁₀, P₅ is an        N-protecting group, and R₁₀ is C₁₋₆ alkyl;    -   (a1) R₂ is H or a hydroxyl protecting group, R₃ is C₁₋₆ alkyl        ether, and R₄ is H;    -   (a2) R₂ is H or a hydroxyl protecting group, and R₃ and R₄        combine to form a double bond;    -   or    -   (a3) R₂ and R₃ combine to form a bond, and R₄ is H;    -   (b1) R₅ is H or a hydroxyl protecting group, and R₆ and R₇        combine to form a double bond;    -   or    -   (b2) R₅ and R₆ combine to form a bond, and R₇ is H;    -   (c1) R₈ is H, and P₄ is H or a hydroxyl protecting group;    -   or    -   (c2) R₈ and P₄ combine to form a double bond;    -   each P₃ is independently H or a hydroxyl protecting group; and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form an aminal or                1,3-oxazolidin-2-one-5-yl.

A compound of the fifth aspect can be a compound of formula (IC):

-   -   or a salt thereof,    -   where    -   each P₃ is independently a hydroxyl protecting group; and        -   X is O, P₁ is a hydroxyl protecting group, and P₂ is H or a            hydroxyl protecting group;        -   or        -   P₁ is a hydroxyl protecting group, and X and P₂ combine to            form optionally masked amino.

A compound of fifth aspect can be a compound of formula (IIA) or (IIB):

-   -   or a salt thereof,    -   where    -   each R is independently optionally substituted alkyl or        optionally substituted aryl;    -   (i) R₁ is H or a hydroxyl protecting group, and R₂ and R₃        combine to form a double bond;    -   or    -   (ii) R₁ and R₂ combine to form a bond, and R₃ is H;    -   each P₃ is independently H or a hydroxyl protecting group, and        X₂ is oxo; or both P₃ groups and X₂, together with the atoms to        which each is attached, combine to form ketal;    -   P₄ is H or a hydroxyl protecting group; and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form an aminal or                1,3-oxazolidin-2-one-5-yl.

A compound of the fifth aspect can be a compound of formula (IIIA) or(IIIB):

-   -   or a salt thereof,    -   where    -   (i) R₁ is H or a hydroxyl protecting group, and R₂ and R₃        combine to form a double bond;    -   or    -   (ii) R₁ and R₂ combine to form a bond, and R₃ is H;    -   X₃ is oxo, or X₃ combines with the carbon atom to which it is        attached to form a ketal, a thioketal, or —(CH(OP₅))—, where P₅        is H or a hydroxyl protecting group;    -   each P₃ is independently H or a hydroxyl protecting group, and        X₂ is oxo; or both P₃ groups and X₂, together with the atoms to        which each is attached, combine to form ketal;    -   P₄ is H or a hydroxyl protecting group; and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form an aminal or                1,3-oxazolidin-2-one-5-yl.

A compound of the fifth aspect can be a compound of formula (IVA) or(IVB):

-   -   or a salt thereof,    -   where    -   Y is iodide, bromide, or trifluoromethanesulfonate;    -   (a1) a designates R stereogenic center, b designates S        stereogenic center, and Z is a sulfonate, chloride, bromide, or        iodide;    -   or    -   (a2) a designates S stereogenic center, b designates R        stereogenic center, and Z is OR₁, where R₁ is a hydroxyl        protecting group;    -   (b1) R₂ is H or a hydroxyl protecting group, and R₃ and R₄        combine to form a double bond;        -   or    -   (b2) R₂ and R₃ combine to form a bond, and R₄ is H;    -   each P₃ is independently H or a hydroxyl protecting group, and        X₂ is oxo; or both P₃ groups and X₂, together with the atoms to        which each is attached, combine to form ketal; and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form an aminal or                1,3-oxazolidin-2-one-5-yl

A compound of the fifth aspect can be a compound of formula (VA) or(VB):

-   -   or a salt thereof,    -   where    -   Y is SO₂R₁ or COOR₁, where, when Y is SO₂R₁, R₁ is optionally        substituted aryl or optionally substituted non-enolizable alkyl,        and when Y is COOR₁, R₁ is optionally substituted alkyl,        optionally substituted aryl, or optionally substituted        arylalkyl;    -   each P₃ is independently H or a hydroxyl protecting group, and        X₂ is oxo, or both P₃ groups and X₂, together with the atoms to        which each is attached, combine to form ketal;    -   R₂ is optionally substituted alkyl, optionally substituted        arylalkyl, or optionally substituted aryl; and    -   X is O, and        -   each of P₁ and P₂ is independently a hydroxyl protecting            group,        -   or        -   P₁ and P₂, together with the atoms to which is each is            attached, combine to form a cyclic protected diol;    -   or    -   X is N, and        -   P₁ is H or a hydroxyl protecting group, and X and P₂ combine            to form optionally masked amino;        -   or        -   P₁ and P₂, together with the atoms to which each is            attached, combine to form an aminal or            1,3-oxazolidin-2-one-5-yl.

A compound of formula (VIA) or (VIB):

-   -   or a salt thereof,    -   where    -   Y is iodide, bromide, or trifluoromethanesulfonate;    -   P₄ is H or a hydroxyl protecting group;    -   (a1) R₃ is H or a hydroxyl protecting group, R₄ and R₅ combine        to form a double bond, each P₃ is independently H or a hydroxyl        protecting group, and X₂, together with the carbon to which it        is attached, forms a carbonyl or —(CH(OR₆))—, where R₆ is H or a        hydroxyl protecting group;    -   or    -   (a2) R₃ and R₄ combine to form a bond, R₅ is H, and        -   each P₃ is independently H or a hydroxyl protecting group,            and X₂, together with the carbon to which it is attached,            forms a carbonyl or —(CH(OR₆))—;        -   or        -   both P₃ groups and X₂, together with the atoms to which each            is attached, combine to form ketal;    -   (b1) Z is chloride, bromide, or iodide, and R₁ and R₂ combine to        form a bond;    -   or    -   (b2) Z and R₂ combine to form a double bond, and R₁ is a        hydroxyl protecting group;    -   and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form an aminal or                1,3-oxazolidin-2-one-5-yl.

A compound of the fifth aspect can be a compound of formula (VIIC):

-   -   or a salt thereof,    -   where    -   Y₁ is SO₂R₁ or COOR₁, and R₁ is optionally substituted alkyl,        optionally substituted aryl, or optionally substituted        arylalkyl;    -   R₂ is —CH₂—OP₃, —CH═CH₂,

-   -   -   where P₃ is H or a hydroxyl protecting group; each P₄ is            independently a hydroxyl protecting group, or both P₄            groups, together with the atoms to which each is attached,            combine to form a cyclic protected diol; and R₄ is H or            —CH₂X₂CH₂CH═CH₂, where X₂ is O, —CH₂—, or NP₅, where P₅ is            sulfonyl;

    -   R₃ is an optionally substituted acyl; and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form an aminal or                1,3-oxazolidin-2-one-5-yl.

A compound of the fifth aspect can be a compound of formula (VIIB):

-   -   where    -   R₃ is —CH₂—OP₃,

-   -   where        -   P₃ is a hydroxyl protecting group; each P₄ is independently            a hydroxyl protecting group, or both P₄ groups, together            with the atoms to which each is attached, combine to form a            cyclic protected diol; and R₄ is H or —CH₂X₂CH₂CH═CH₂, where            X₂ is O, —CH₂—, or NP₅, where P₅ is sulfonyl.

A compound of the fifth aspect can be a compound of formula (IVE):

-   -   where    -   Y is iodide, bromide, or trifluoromethanesulfonate;    -   Z is an ester, a sulfonate, chloride, bromide, or iodide;    -   each P₃ is independently H or a hydroxyl protecting group, and        X₂ is oxo; or both P₃ groups and X₂, together with the atoms to        which each is attached, combine to form ketal; and    -   (a1) R₂ is H or a hydroxyl protecting group, R₃ and R₄ combine        to form a double bond;    -   or    -   (a2) R₂ and R₃ combine to form a bond, and R₄ is H;    -   (b1) R₇ and R₈ combine to form a bond, and R₉ is H;    -   or    -   (b2) R₇ is H or a hydroxyl protecting group, and R₈ and R₉        combine to form a double bond;    -   (c1) X₃ is oxo and R₁₀ is H or —OP₅, where P₅ is H or an ether        hydroxyl protecting group;    -   or    -   (c2) X₃ and R₁₀ together with the carbon atom to which they are        attached form —CH₂OP₆, wherein P₆ is H or a hydroxyl protecting        group, and R₁₀ is H.        Definitions

Compounds useful in the invention may be isotopically labeled compounds.Useful isotopes include hydrogen, carbon, nitrogen, and oxygen (e.g.,²H, ³H, ¹³C, ¹⁴C, ¹⁵N, and ¹⁷O). Isotopically-labeled compounds can beprepared by synthesizing a compound using a readily availableisotopically-labeled reagent in place of a non-isotopically-labeledreagent.

For any of the following chemical definitions, a number following anatomic symbol indicates that total number of atoms of that element thatare present in a particular chemical moiety. As will be understood,other atoms, such as hydrogen atoms, or substituent groups, as describedherein, may be present, as necessary, to satisfy the valences of theatoms. For example, an unsubstituted C₂ alkyl group has the formula—CH₂CH₃. When used with the groups defined herein, a reference to thenumber of carbon atoms includes the divalent carbon in acetal and ketalgroups but does not include the carbonyl carbon in acyl, ester,carbonate, or carbamate groups. A reference to the number of oxygen,nitrogen, or sulfur atoms in a heteroaryl group only includes thoseatoms that form a part of a heterocyclic ring.

By “acetal” is meant —O—(CHR)—O—, where R is H, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted aryl, oroptionally substituted arylalkyl.

By “acyl” is meant —C(O)R, where R is H, alkyl, alkenyl, aryl, orarylalkyl. In exemplary acyl groups, R is H, C₁₋₁₂ alkyl (e.g., C₁₋₈,C₁₋₆, C₁₋₄, C₂₋₇, C₃₋₁₂, or C₃₋₆ alkyl), C₂₋₁₂ alkenyl (e.g., C₂₋₈,C₂₋₆, C₂₋₄, C₃₋₁₂, or C₃₋₆ alkenyl), C₆₋₂₀ aryl (e.g., C₆₋₁₅, C₆₋₁₀,C₈₋₂₀, or C₈₋₁₅ aryl), monocyclic C₁₋₆ heteroaryl (e.g., monocyclic C₁₋₄or C₂₋₆ heteroaryl), C₄₋₁₉ heteroaryl (e.g., C₄₋₁₀ heteroaryl),(C₆₋₁₅)aryl(C₁₋₆)alkyl, (C₁₋₆)heteroaryl(C₁₋₆)alkyl, or(C₄₋₁₉)heteroaryl(C₁₋₆)alkyl. As defined herein, any heteroaryl grouppresent in an acyl group has from 1 to 4 heteroatoms selectedindependently from O, N, and S. An acyl group can be unsubstituted orsubstituted (e.g., optionally substituted acyl). In the optionallysubstituted acyl group, the substituent R is H, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted aryl, oroptionally substituted arylalkyl.

By “acylating agent” is meant a compound that reacts with an amine or ahydroxyl group to produce an amide or an ester, respectively. Anacylating agent has a formula R-LG, where R is acyl, and LG is halogen,carbonate, or —OR′, where R′ is acyl.

By “alkoxide” is meant an anionic compound RO⁻, where R is alkyl. Acounterion for alkoxide can be an alkali metal cation, an alkali earthmetal cation, or a tetraalkylammonium cation. Alkoxide can be optionallysubstituted in the same manner as alkyl.

By “alkoxy” is meant —OR, where R is alkyl. Alkoxy can be optionallysubstituted in the same manner as alkyl.

By “alkoxyalkyl” is meant —OR, where R is alkyl substituted by alkoxy.Each portion of the alkoxyalkyl can be optionally substituted in thesame manner as alkyl.

By “alkyl” is meant a straight or branched chain saturated cyclic (i.e.,cycloalkyl) or acyclic hydrocarbon group of from 1 to 12 carbons, unlessotherwise specified. Exemplary alkyl groups include C₁₋₈, C₁₋₆, C₁₋₄,C₂₋₇, C₃₋₁₂, and C₃₋₆ alkyl. Specific examples include methyl, ethyl,1-propyl, 2-propyl, 2-methyl-1-propyl, 1-butyl, 2-butyl, and the like.Alkyl group can be optionally substituted with 1, 2, 3, or 4substituents selected from the group consisting of halogen, alkoxy,aryloxy, arylalkyloxy, oxo, alkylthio, alkylenedithio, alkylamino,[alkenyl]alkylamino, [aryl]alkylamino, [arylalkyl]alkylamino,dialkylamino, silyl, sulfonyl, cyano, nitro, carboxyl, and azido.

By “alkylamino” is meant —NHR, where R is alkyl. By“[alkenyl]alkylamino” is meant —NRR′, where R is alkyl, and R′ isalkenyl. By “[aryl]alkylamino” is meant —NRR′, where R is alkyl, and R′is aryl. By “[arylalkyl]alkylamino” is meant —NRR′, where R is alkyl,and R′ is arylalkyl. By “dialkylamino” is meant —NR₂, where each R isalkyl, selected independently.

By “alkylene” is meant a divalent alkyl group. Alkylene groups can beoptionally substituted in the same manner as alkyl groups. For example,a C₁ alkylene group is —CH₂—.

By “alkylenedithio” is meant —S-alkylene-S—. Alkylenedithio can beoptionally substituted in the same manner as an alkylene group.

By “alkylthio” is meant —SR, where R is alkyl. Alkylthio can beoptionally substituted in the same manner as an alkyl group.

By “alkenyl” is meant a straight or branched chain cyclic or acyclichydrocarbon group of, unless otherwise specified, from 2 to 12 carbonsand containing one or more carbon-carbon double bonds. Exemplary alkenylgroups include C₂₋₈, C₂₋₇, C₂₋₆, C₂₋₄, C₃₋₁₂, and C₃₋₆ alkenyl. Specificexamples include ethenyl (i.e., vinyl), 1-propenyl, 2-propenyl (i.e.,allyl), 2-methyl-1-propenyl, 1-butenyl, 2-butenyl (i.e., crotyl), andthe like. Alkenyl group can be optionally substituted in the same manneras alkyl groups. Alkenyl groups, used in any context herein, may also besubstituted with an aryl group.

By “amido” is meant —NHR, where R is acyl. Amido can be optionallysubstituted in the same manner as acyl.

By “aminal” is meant —O—CR₂—NR′—, where each R is independently H,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted aryl, or optionally substituted arylalkyl, or both R groupsare together optionally substituted alkylene, and R′ is H or anN-protecting group. In particular, R′ can be an N-protecting group(e.g., Boc).

By “amino” is meant —NR₂, where N and R₂ combine to form azido, or eachR is independently H or an N-protecting group, or both R combine to forman N-protecting group. Amino can be unmasked, when each R is H, ormasked, when at least one R is not H. Thus, optionally masked amino canbe masked or unmasked amino.

By “aryl” is meant a monocyclic or multicyclic ring system having one ormore aromatic rings, where the ring system is carbocyclic orheterocyclic. Heterocyclic aryl groups are also referred to asheteroaryl groups. A heteroaryl group includes 1 to 4 atoms selectedindependently from O, N, and S. Exemplary carbocyclic aryl groupsinclude C₆₋₂₀, C₆₋₁₅, C₆₋₁₀, C₈₋₂₀, and C₈₋₁₅ aryl. A preferred arylgroup is a C6-10 aryl group. Specific examples of carbocyclic arylgroups include phenyl, indanyl, indenyl, naphthyl, phenanthryl,anthracyl, and fluorenyl. Exemplary heteroaryl groups include monocylicrings having from 1 to 4 heteroatoms selected independently from O, N,and S and from 1 to 6 carbons (e.g., C₁₋₆, C₁₋₄, and C₂₋₆). Monocyclicheteroaryl groups preferably include from 5 to 9 ring members. Otherheteroaryl groups preferably include from 4 to 19 carbon atoms (e.g.,C₄₋₁₀). Specific examples of heteroaryl groups include pyridinyl,quinolinyl, dihydroquinolinyl, isoquinolinyl, quinazolinyl,dihydroquinazolyl, and tetrahydroquinazolyl. Aryl group can beoptionally substituted with 1, 2, 3, 4, or 5 substituents selected fromthe group consisting of alkyl, alkenyl, aryl, arylalkyl, halogen,alkoxy, aryloxy, arylalkyloxy, alkylthio, alkylenedithio, alkylamino,[alkenyl]alkylamino, [aryl]alkylamino, [arylalkyl]alkylamino,dialkylamino, silyl, sulfonyl, cyano, nitro, carboxyl, and azido.

By “arylalkyl” is meant —R′R″, where R′ is alkylene, and R″ is aryl.Arylalkyl can be optionally substituted in the same manner as definedfor each R′ and R″ group.

By “arylalkyloxy” is meant —OR, where R is arylalkyl. Arylalkyloxy canbe optionally substituted in the same manner as defined for arylalkyl.

By “aryloxy” is meant —OR, where R is aryl. Aryloxy can be optionallysubstituted in the same manner as aryl.

By “azido” is meant —N₃.

By “boronate” is meant —OBRO—, where R is alkyl, alkenyl, aryl,arylalkyl, alkoxy, or 2,6-diacetamidophenyl. Boronate can besubstituted, when R is a substituted alkyl, substituted alkenyl,substituted aryl, substituted arylalkyl, or substituted alkoxy.Alternatively, boronate can be unsubstituted, when R is unsubstitutedalkyl, unsubstituted alkenyl, aryl, unsubstituted arylalkyl,unsubstituted alkoxy, or 2,6-diacetamidophenyl.

By “carbamate” is meant a group, when a hydroxyl protecting group,having the formula —OC(O)NR₂, or, when an amine protecting group, havingthe formula —NR′—C(O)OR, where each R and R′ is independently H,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted aryl, or optionally substituted arylalkyl.

By “carbonate” is meant —OC(O)OR, where R is optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted aryl, oroptionally substituted arylalkyl.

By “carbonyl” is meant —C(O)—.

By “carboxyl” is meant —C(O)OH, in free acid, ionized, or salt form.

By “carboxylic acid” is meant R—OH, where R is optionally substitutedacyl.

By “carboxylic acid anhydride” is meant R—O—R, where each R isindependently optionally substituted acyl.

By “dicarbonyl” is meant —C(O)—C(O)—.

By “ester” is meant —OC(O)R, where —C(O)R is an optionally substitutedacyl group.

By “ether” is meant —OR, where R is alkyl, alkenyl, arylalkyl, silyl, or2-tetrahydropyranyl. Ether can be optionally substituted as defined foreach R group.

By “halogen” is meant fluoro, chloro, bromo, or iodo.

By “hydroxyl protecting group” is meant any group capable of protectingthe oxygen atom to which it is attached from reacting or bonding.Hydroxyl protecting groups are known in the art, e.g., as described inWuts, Greene's Protective Groups in Organic Synthesis,Wiley-Interscience, 4th Edition, 2006. Exemplary protecting groups (withthe oxygen atom to which they are attached) are independently selectedfrom the group consisting of esters, carbonates, carbamates, sulfonates,and ethers. In exemplary ester hydroxyl protecting groups, R of the acylgroup is C₁₋₁₂ alkyl (e.g., C₁₋₈, C₁₋₆, C₁₋₄, C₂₋₇, C₃₋₁₂, and C₃₋₆alkyl), C₂₋₁₂ alkenyl (e.g., C₂₋₈, C₂₋₆, C₂₋₄, C₃₋₁₂, and C₃₋₆ alkenyl),carbocyclic C₆₋₂₀ aryl (e.g., C₆₋₁₅, C₆₋₁₀, C₈₋₂₀, and C₈₋₁₅ aryl),monocyclic C₁₋₆ heteroaryl (e.g., C₁₋₄ and C₂₋₆ heteroaryl), C₄₋₁₉heteroaryl (e.g., C₄₋₁₀ heteroaryl), (C₆₋₁₅)aryl(C₁₋₆)alkyl,(C₄₋₁₉)heteroaryl(C₁₋₆)alkyl, or (C₁₋₆)heteroaryl(C₁₋₆)alkyl. Specificexamples of acyl groups for use in esters include formyl, benzoylformyl,acetyl (e.g., unsubstituted or chloroacetyl, trifluoroacetyl,methoxyacetyl, triphenylmethoxyacetyl, and p-chlorophenoxyacetyl),3-phenylpropionyl, 4-oxopentanoyl, 4,4-(ethylenedithio)pentanoyl,pivaloyl (Piv), vinylpivaloyl, crotonoyl, 4-methoxy-crotonoyl, naphthoyl(e.g., 1- or 2-naphthoyl), and benzoyl (e.g., unsubstituted orsubstituted, e.g., p-methoxybenzoyl, phthaloyl (including salts, such atriethylamine and potassium), p-bromobenzoyl, and2,4,6-trimethylbenzoyl). As defined herein, any heteroaryl group presentin an ester group has from 1 to 4 heteroatoms selected independentlyfrom O, N, and S. In exemplary carbonate hydroxyl protecting groups, Ris C₁₋₁₂ alkyl (e.g., C₁₋₈, C₁₋₆, C₁₋₄, C₂₋₇, C₃₋₁₂, and C₃₋₆ alkyl),C₂₋₁₂ alkenyl (e.g., C₂₋₈, C₂₋₆, C₂₋₄, C₃₋₁₂, and C₃₋₆ alkenyl),carbocyclic C₆₋₂₀ aryl (e.g., C₆₋₁₅, C₆₋₁₀, C₈₋₂₀, and C₈₋₁₅ aryl),monocyclic C₁₋₆ heteroaryl (e.g., C₁₋₄ and C₂₋₆ heteroaryl), C₄₋₁₉heteroaryl (e.g., C₄₋₁₀ heteroaryl), (C₆₋₁₅)aryl(C₁₋₆)alkyl,(C₄₋₁₉)heteroaryl(C₁₋₆)alkyl, or (C₁₋₆)heteroaryl(C₁₋₆)alkyl. Specificexamples include methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl,2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, t-butyl,p-nitrobenzyl, and benzyl carbonates. As defined herein, any heteroarylgroup present in a carbonate group has from 1 to 4 heteroatoms selectedindependently from O, N, and S. In exemplary carbamate hydroxylprotecting groups, each R is independently H, C₁₋₁₂ alkyl (e.g., C₁₋₈,C₁₋₆, C₁₋₄, C₂₋₇, C₃₋₁₂, and C₃₋₆ alkyl), C₂₋₁₂ alkenyl (e.g., C₂₋₈,C₂₋₆, C₂₋₄, C₃₋₁₂, and C₃₋₆ alkenyl), carbocyclic C₆₋₂₀ aryl (e.g.,C₆₋₁₅, C₆₋₁₀, C₈₋₂₀, and C₈₋₁₅ aryl), monocyclic C₁₋₆ heteroaryl (e.g.,C₁₋₄ and C₂₋₆ heteroaryl), C₄₋₁₉ heteroaryl (e.g., C₄₋₁₀ heteroaryl),(C₆₋₁₅)aryl(C₁₋₆)alkyl, (C₄₋₁₉)heteroaryl(C₁₋₆)alkyl, or(C₁₋₆)heteroaryl(C₁₋₆)alkyl. Specific examples include N-phenyl andN-methyl-N-(o-nitrophenyl) carbamates. As defined herein, any heteroarylgroup present in a carbamate group has from 1 to 4 heteroatoms selectedindependently from O, N, and S. Exemplary ether hydroxyl protectinggroups include C₁₋₁₂ alkyl (e.g., C₁₋₈, C₁₋₆, C₁₋₄, C₂₋₇, C₃₋₁₂, andC₃₋₆ alkyl), C₂₋₁₂ alkenyl (e.g., C₂₋₈, C₂₋₆, C₂₋₄, C₃₋₁₂, and C₃₋₆alkenyl), (C₆₋₁₅)aryl(C₁₋₆)alkyl, (C₄₋₁₉)heteroaryl(C₁₋₆)alkyl,(C₁₋₆)heteroaryl(C₁₋₆)alkyl, (C₁₋₆)alkoxy(C₁₋₆)alkyl,(C₁₋₆)alkylthio(C₁₋₆)alkyl, (C₆₋₁₀)aryl(C₁₋₆)alkoxy(C₁₋₆)alkyl, andsilyl (e.g., tri(C₁₋₆ alkyl)silyl, tri(C₆₋₁₀ aryl or C₁₋₆heteroaryl)silyl, di(C₆₋₁₀ aryl or C₁₋₆ heteroaryl)(C₁₋₆ alkyl)silyl,and (C₆₋₁₀ aryl or C₁₋₆ heteroaryl)di(C₁₋₆ alkyl)silyl). Specificexamples of alkylethers include methyl and t-butyl, and an example of analkenyl ether is allyl. Ether hydroxyl protecting groups can be used toprotect a carboxyl group (e.g., with a C₁₋₁₂ alkyl (e.g., C₁₋₈, C₁₋₆,C₁₋₄, C₂₋₇, C₃₋₁₂, and C₃₋₆ alkyl), (C₆₋₁₅)aryl(C₁₋₆)alkyl,(C₁₋₆)alkoxy(C₁₋₆)alkyl, (C₁₋₆)alkylthio(C₁₋₆)alkyl, or(C₆₋₁₀)aryl(C₁₋₆)alkoxy(C₁₋₆)alkyl). Examples of alkoxyalkyls andalkylthioalkyls that can be used as ether hydroxyl protecting groupsinclude methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, andβ-(trimethylsilyl)ethoxymethyl. Examples of arylalkyl groups that can beused as ether hydroxyl protecting groups include benzyl, p-methoxybenzyl(MPM), 3,4-dimethoxybenzyl, triphenylmethyl (trityl), o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl,naphthylmethyl, and 2- and 4-picolyl ethers. Specific examples ofsilylethers include trimethylsilyl (TMS), triethylsilyl (TES),t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl (TBDPS),triisopropylsilyl (TIPS), and triphenylsilyl (TPS) ethers. An example ofan arylalkyloxyalkylether is benzyloxymethyl ether. As defined herein,any heteroaryl group present in an ether group has from 1 to 4heteroatoms selected independently from O, N, and S. Vicinal or1,3-diols may be protected with a diol protecting group (e.g., toproduce a “cyclic protected diol”), such as acetal (e.g., containingC₁₋₆ alkylene), ketal (e.g., containing C₃₋₆ alkylene or C₃₋₆cycloalkyl), cyclic silylene, cyclic carbonate, and cyclic boronate.Examples of acetal and ketal groups include methylene-dioxo,ethylidene-dioxo, benzylidene-dioxo, isopropylidene-dioxo,cyclohexylidene-dioxo, and cyclopentylidene-dioxo. An example of acyclic silylene is di-t-butylsilylene. Another diol protecting group is1,1,3,3-tetraisopropylsiloxanediyl. Examples of cyclic boronates includemethyl, ethyl, phenyl, and 2,6-diacetamidophenyl boronates. Protectinggroups may be substituted as is known in the art; for example, aryl andarylalkyl groups, such as phenyl, benzyl, naphthyl, or pyridinyl, can besubstituted with C₁₋₆ alkyl, C₁₋₆ alkoxy, nitro, cyano, carboxyl, orhalogen. Alkyl groups, such as methyl, ethyl, isopropyl, n-propyl,t-butyl, n-butyl, and sec-butyl, and alkenyl groups, such as vinyl andallyl, can also be substituted with oxo, arylsulfonyl, halogen, andtrialkylsilyl groups. Preferred protecting groups are TBS and Piv.Protecting groups that are orthogonal are removed under differentconditions, as in known in the art.

By “imido” is meant —NR₂, where each R is independently optionallysubstituted acyl.

By “ketal” is meant —O—CR₂—O—, where each R is independently optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted aryl, or optionally substituted arylalkyl, or both R groupsare together optionally substituted alkylene.

By “macrocyclization” is meant a reaction converting a non-macrocycliccompound into a compound containing at least one n-membered ring, wheren is equal to or greater than 16.

By “non-enolizable” is meant a group that, either alone or incombination with a group to which it is attached, cannot form an enolthrough a deprotonation/reprotonation sequence. For example, a“non-enolizable alkyl” can be bonded to a sulfone group or to a carbonylgroup through a quaternary carbon atom (i.e., the carbon atom that isnot bonded to a hydrogen atom).

By “non-macrocyclic” is meant a compound not containing rings orcontaining one or more m-membered rings, where m is less than or equalto 15.

By “N-protecting group” is meant a group protecting a nitrogen atom in amolecule from participating in one or more undesirable reactions duringchemical synthesis (e.g., oxidation reactions, or certain nucleophilicand electrophilic substitutions). Commonly used N-protecting groups aredisclosed in Wuts, Greene's Protective Groups in Organic Synthesis,Wiley-Interscience, 4th Edition, 2006. Exemplary N-protecting groupsinclude acyl (e.g., formyl, acetyl, trifluoroacetyl, propionyl,pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl,trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl,benzoyl, 4-chlorobenzoyl, and 4-bromobenzoyl); sulfonyl-containinggroups (e.g., benzenesulfonyl, p-toluenesulfonyl,o-nitrobenzenesulfonyl, and p-nitrobenzenesulfonyl); carbamate forminggroups (e.g., benzyloxycarbonyl, p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyl oxycarbonyl,2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl,t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl),arylalkyl (e.g., triphenylmethyl); silyl groups (e.g., trimethylsilyl);and imine-forming groups (e.g., diphenylmethylene). PreferredN-protecting groups are acetyl, benzoyl, phenylsulfonyl,p-toluenesulfonyl, p-nitrobenzenesulfonyl, o-nitrobenzenesulfonyl,t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

By “1,3-oxazolidin-2-one-5-yl” is meant 1,3-oxazolidin-2-one-5-yl, inwhich the nitrogen atom is substituted with H or an N-protecting group(e.g., Boc).

By “oxo” or (0) is meant ═O.

By “pharmaceutically acceptable salt” is meant a salt within the scopeof sound medical judgment, suitable for use in contact with the tissuesof humans and animals without undue toxicity, irritation, allergicresponse and the like and commensurate with a reasonable benefit/riskratio. Pharmaceutically acceptable salts are well known in the art. Forexample, pharmaceutically acceptable salts are described in: Berge etal., J. Pharmaceutical Sciences 66:1-19, 1977 and in PharmaceuticalSalts: Properties, Selection, and Use, (Eds. P. H. Stahl and C. G.Wermuth), Wiley-VCH, 2008. Representative acid addition salts includeacetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate,benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,citrate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, fumarate, glucoheptonate, glycerophosphate,hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride,hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate,lauryl sulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, toluenesulfonate, undecanoate, valerate salts and the like.A preferred salt is the mesylate salt.

By “silyl” is meant —SiR₃, where each R is independently alkyl, alkenyl,aryl, or arylalkyl. Examples of silyl groups include tri(C₁₋₆alkyl)silyl, tri(C₆₋₁₀ aryl or C₁₋₆ heteroaryl)silyl, di(C₆₋₁₀ aryl orC₁₋₆ heteroaryl)(C₁₋₆ alkyl)silyl, and (C₆₋₁₀ aryl or C₁₋₆heteroaryl)di(C₁₋₆ alkyl)silyl. It will be understood that, when a silylgroup includes two or more alkyl, alkenyl, aryl, heteroaryl, orarylalkyl groups, these groups are independently selected. As definedherein, any heteroaryl group present in a silyl group has from 1 to 4heteroatoms selected independently from O, N, and S. Silyl can beoptionally substituted in the same manner as defined for each R group.

By “silylene” is meant —SiR₂—, where each R is independently alkyl,alkenyl, aryl, arylalkyl, or alkoxy. By “dialkylsilylene” is meant asilylene, where each R is alkyl. Silylene can be optionally substitutedin the same manner as defined for each R group.

By “strong base” is meant a Brønsted base, the conjugate acid of whichhas pKa that is greater than or equal to 13. Non-limiting examples ofstrong bases include alkyl alkali metals (e.g., butyl lithium orSchlosser's base), Grignard reagents (e.g., alkyl magnesium halide),alkoxides (e.g., tertiary alkoxides, such as t-butoxide), amides (e.g.,diisopropylamide, tetramethylpiperidide, or bis(trimethylsilyl)amide),and phosphazene bases (e.g., Schwesinger base).

By “sulfonamide” is meant —NR, where R is sulfonyl.

By “sulfonate” is meant —OS(O)₂R, where R is optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted aryl, oroptionally substituted arylalkyl. In exemplary sulfonates, R is C₁₋₁₂alkyl (e.g., C₁₋₈, C₁₋₆, C₁₋₄, C₂₋₇, C₃₋₁₂, or C₃₋₆ alkyl), C₂₋₁₂alkenyl (e.g., C₂₋₈, C₂₋₆, C₂₋₄, C₃₋₁₂, or C₃₋₆ alkenyl), carbocyclicC₆₋₂₀ aryl (e.g., C₆₋₁₅, C₆₋₁₀, C₈₋₂₀, or C₈₋₁₅ aryl), monocyclic C₁₋₆heteroaryl (e.g., C₁₋₄ and C₂₋₆ heteroaryl), C₄₋₁₉ heteroaryl (e.g.,C₄₋₁₀ heteroaryl), (C₆₋₁₅)aryl(C₁₋₆)alkyl, (C₄₋₁₉)heteroaryl(C₁₋₆)alkyl,or (C₁₋₆)heteroaryl(C₁₋₆)alkyl. As defined herein, any heteroaryl grouppresent in a sulfonate group has from 1 to 4 heteroatoms selectedindependently from O, N, and S.

By “sulfonyl” is meant —S(O)₂R, where R is optionally substituted alkyl,optionally substituted alkenyl, optionally substituted aryl, optionallysubstituted arylalkyl, or silyl. Preferred R groups for sulfonyl are thesame as those described above for sulfonates.

By “thioacetal” is meant —S—(CHR)—S—, where R is H, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted aryl, or optionally substituted arylalkyl.

By “thioketal” is meant —S—(CR₂)—S—, where each R is independentlyoptionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted aryl, or optionally substituted arylalkyl.

By “triflate” is meant trifluoromethanesulfonate.

The pKa values recited herein refer to the pKa values of a conjugateBrønsted acid in water at room temperature, unless stated otherwise.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a scheme showing preparation of eribulin through a C.15-C.16bond-forming macrocyclization.

FIG. 2 is a scheme showing preparation of eribulin through a C.2-C.3bond-forming macrocyclization.

FIG. 3 is a scheme showing preparation of eribulin through a C.3-C.4bond-forming macrocyclization.

FIG. 4 is a scheme showing preparation of eribulin through a C.19-C.20bond-forming macrocyclization.

FIG. 5 is a scheme showing preparation of eribulin through a C.0-C.1bond-forming macrocyclization.

FIG. 6 is a scheme showing preparation of eribulin through a C.26-C.27bond-forming macrocyclization.

FIG. 7 is a depiction of a co-crystal of2-((2R,3S,3aS,4aS,7R,8aR,9S,9aS)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3,9-dihydroxydecahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethylpivalate and its C3-epimer.

DETAILED DESCRIPTION

The present invention provides methods for the synthesis of eribulin ora pharmaceutically acceptable salt thereof (e.g., eribulin mesylate)through a macrocyclizations. The macrocyclizations of the presentinvention involve subjecting a non-macrocyclic intermediate to acarbon-carbon bond-forming reaction (e.g., catalytic Ring-Closing OlefinMetathesis, an olefination reaction (e.g., Horner-Wadsworth-Emmonsolefination), Nozaki-Hiyama-Kishi reaction, or Dieckmann reaction) toafford a macrocyclic intermediate (e.g., a compound of formula (IB),(IIB), (IIIB), (IVB), (VB), or (VIB)). The carbon-carbon bond formingreaction provides a C.0-C.1, C.2-C.3, C.3-C.4, C.15-C.16, C.19-C.20, orC.26-C.27 bond in the structure of eribulin or a pharmaceuticallyacceptable salt thereof. The carbon-atom numbering scheme for eribulinand pharmaceutically acceptable salts thereof is shown in Chart 1.

The invention also provides intermediates in the synthesis of eribulinand methods of preparing the same, as described herein.

C.15-C.16 Bond-Forming Macrocyclization

The macrocyclization reaction of the invention can be a carbon-carbonbond-forming reaction (e.g., catalytic Ring-Closing olefin Metathesis(RCM)) that provides a C.15-C.16 bond in eribulin or a pharmaceuticallyacceptable salt thereof (e.g., eribulin mesylate). The general syntheticsequence including RCM that can be used to prepare eribulin or apharmaceutically acceptable salt thereof (e.g., a mesylate salt) isshown in FIG. 1. As shown in FIG. 1, the non-macrocyclic intermediate inthe synthesis of eribulin can be a compound of formula (IA):

-   -   where    -   R₁ is H or —CH₂X₁CH₂CH═CH₂, wherein X₁ is O, —C(R₉)₂—, or NP₅,        and where each R₉ is independently H or —COOR₁₀, P₅ is an        N-protecting group, and R₁₀ is C₁₋₆ alkyl;    -   (a1) R₂ is H or a hydroxyl protecting group, R₃ is C₁₋₆ alkyl        ether, and R₄ is H;    -   (a2) R₂ is H or a hydroxyl protecting group, and R₃ and R₄        combine to form a double bond;    -   or    -   (a3) R₂ and R₃ combine to form a bond, and R₄ is H;    -   (b1) R₅ is H or a hydroxyl protecting group, and R₆ and R₇        combine to form a double bond;    -   or    -   (b2) R₅ and R₆ combine to form a bond, and R₇ is H;    -   (c1) R₈ is H, and P₄ is H or a hydroxyl protecting group;    -   or    -   (c2) R₈ and P₄ combine to form a double bond;    -   each P₃ is independently H or a hydroxyl protecting group; and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form an aminal or                1,3-oxazolidin-2-one-5-yl.

An intermediate in the synthesis of eribulin can be a compound offormula (IB), which can be produced by reacting the compound of formula(IA) with an olefin metathesis catalyst (e.g., a ruthenium-carbenecomplex). The compound of formula (IB) has the following structure:

-   -   where all variables are as defined for compound of formula (IA).

The catalysts that can be used to convert the compound of formula (IA)to the compound of formula (IB) can be those known in the art. Olefinmetathesis catalysts include Ru-carbene complexes (e.g., Grubbs andHoveyda-Grubbs catalysts).

The compound of formula (IB) can be reacted with a hydroxyl protectinggroup removing agent and, optionally, an oxidizing agent (e.g., when R₈is H in the compound of formula (IB)) capable of converting an alcoholto a carbonyl group (e.g., capable of converting an allylic alcohol toan enone) to afford the compound of formula (IC):

-   -   where P₁, P₂, P₃, and X are as defined for compound of formula        (IB).

The hydroxyl protecting group removing agent used in the step formingthe compound of formula (IC) can be a Brønsted acid (e.g., a carboxylicacid, such as a carboxylic acid having a pKa of 4±1).

The compound of formula (ID) can be prepared from the compound offormula (IC) by a synthesis involving reacting the compound of formula(IC) with a 1,4-reducing agent to afford a compound of formula (ID):

-   -   where P₁, P₂, and X are as defined for compound of formula (IC);        and    -   each P₃ is independently H or a hydroxyl protecting group, and        X₂ is oxo; or both P₃ groups and X₂, together with the atoms to        which each is attached, combine to form ketal.

The 1,4-reducing agents include copper (I) hydrides, which can beisolated (e.g., Stryker's reagent) or prepared in situ (e.g., from acopper (I) or copper (II) salt and a hydride source). Catalyticquantities of a copper salt (either copper (I) or copper (II) salt) incombination with stoichiometric or superstoichiometric quantities of ahydride source (e.g., a borohydride salt, borane, PMHS, or a hydrosilane(e.g., Ph₂SiH₂)). A non-limiting example of the reaction conditions thatcan be used for conversion of the compound of formula (IC) to thecompound of formula (ID) are described, e.g., in Baker et al., Org.Lett., 10:289-292, 2008, the disclosure of which is incorporated hereinby reference. Other metals can be used to catalyze 1,4-reduction of thecompound of formula (IC) to afford the compound of formula (ID), e.g.,Ru, Pd, and Ir compounds.

If P₁ is a hydroxyl protecting group in the compound of formula (ID),the compound of formula (ID) can be reacted with a hydroxyl protectinggroup removing agent to afford:

-   -   where    -   both P₃ groups and X₂, together with the atoms to which each is        attached, combine to form ketal; and        -   X is O, and each of P₁ and P₂ is H,        -   or        -   P₁ is H, and X and P₂ combine to form optionally masked            amino.

The compound of formula (ID) (e.g., the compound of formula (ID), inwhich X is O, P₂ is H, and both P₃ groups and X₂, together with theatoms to which each is attached, combine to form ketal) can be aminatedto afford eribulin, e.g., using sulfonylation followed by the treatmentwith a nitrogen source (e.g., ammonia (e.g., aqueous ammonia) orsulfamic acid). When the nitrogen source is not ammonia or sulfamicacid, further contacting with an amino unmasking agent may be used toafford eribulin. The compound of formula (ID), in which P₁ is a hydroxylprotecting group, can be reacted with a hydroxyl protecting groupremoving agent prior to the amination reaction. Alternatively, thecompound of formula (ID) (in which P₁ is H, X and P₂ combine to form amasked amino, and both P₃ groups and X₂, together with the atoms towhich each is attached, combine to form ketal) can be reacted with anamino unmasking agent to afford eribulin, as described herein. Eribulinmesylate can then be produced by salification of eribulin withmethanesulfonic acid. The details of the amination and salificationreactions are described below.

The compound of formula (IA) can be prepared from a compound of formula(IE):

-   -   where    -   R₁ is H or —CH₂X₁CH₂CHCH₂, wherein X₁ is O, —C(R₉)₂—, or NP₅,        and where each R₉ is independently H or —COOR₁₀, P₅ is an        N-protecting group, and R₁₀ is C₁₋₆ alkyl;    -   (a1) R₂ is H or a hydroxyl protecting group, R₃ is C₁₋₆ alkyl        ether, and R₄ is H;    -   (a2) R₂ is H or a hydroxyl protecting group, and R₃ and R₄        combine to form a double bond;    -   or    -   (a3) R₂ and R₃ combine to form a bond, and R₄ is H;    -   (b1) R₅ is H or a hydroxyl protecting group, and R₆ and R₇        combine to form a double bond;    -   or    -   (b2) R₅ and R₆ combine to form a bond, and R₇ is H;    -   (c1) R₈ is H, and P₄ is H or a hydroxyl protecting group;    -   or    -   (c2) R₈ and P₄ combine to form a double bond;    -   each P₃ is independently H or a hydroxyl protecting group;    -   Y is SO₂R₁₁ and R₁₁ is optionally substituted aryl or optionally        substituted non-enolizable alkyl; or

Y is COOR₁₁, and R₁₁ is optionally substituted alkyl, optionallysubstituted aryl, or optionally substituted arylalkyl;

-   -   X₃ is oxo, or X₃, together with the carbon atom to which it is        attached, forms —(CH(OH))—; and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form an aminal or                1,3-oxazolidin-2-one-5-yl.

In some embodiments, the preparation of the compound of formula (IA)from the compound of formula (IE) involves a decarboxylation reaction(when X₃ is oxo, and Y is COOR₁₁) or a desulfonylation (when X₃ is oxo,and Y is SO₂R₁₁) reaction. The conditions for the decarboxylation ordesulfonylation reaction can be those described herein. The preparationof the compound of formula (IA) from the compound of formula (IE) canfurther involve oxidizing the compound of formula (IE) (e.g., thecompound of formula (IE), in which X₃, together with the carbon atom towhich it is attached, forms —(CH(OH))—), e.g., by contacting with anoxidizing agent capable of oxidizing an alcohol to a carbonyl group.

C.2-C.3 Bond-Forming Macrocyclization

The macrocyclization reaction of the invention can be a carbon-carbonbond-forming reaction (e.g., Horner-Wadsworth-Emmons reaction) thatprovides a C.2-C.3 bond in eribulin or a pharmaceutically acceptablesalt thereof (e.g., eribulin mesylate). The general synthetic sequenceincluding the Horner-Wadsworth-Emmons reaction that can be used toprepare eribulin or a pharmaceutically acceptable salt thereof (e.g., amesylate salt) is shown in FIG. 2. As shown in FIG. 2, thenon-macrocyclic intermediate can be a compound of formula (IIA):

-   -   where    -   each R is independently optionally substituted alkyl or        optionally substituted aryl;    -   (i) R₁ is H or a hydroxyl protecting group, and R₂ and R₃        combine to form a double bond;    -   or    -   (ii) R₁ and R₂ combine to form a bond, and R₃ is H;    -   each P₃ is independently H or a hydroxyl protecting group, and        X₂ is oxo; or both P₃ groups and X₂, together with the atoms to        which each is attached, combine to form ketal;    -   P₄ is H or a hydroxyl protecting group; and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form an aminal or                1,3-oxazolidin-2-one-5-yl.

The intermediate in the synthesis of eribulin can be a compound offormula (IIB), which can be produced from the compound of formula (IIA)using Horner-Wadsworth-Emmons reaction. The compound of formula (IIB)has the following structure:

-   -   where all variables are as defined for the compound of formula        (IIA).

The reaction conditions that can be used to convert the compound offormula (IIA) into the compound of formula (IIB) include those known inthe art for Horner-Wadsworth-Emmons reaction, e.g., Masamune-Roushconditions or Helquist protocol. In particular, the compound of formula(IIA) can be reacted with an organic base (e.g., an organic base, theconjugate acid of which has a pKa of from 11±2) and a Lewis acid (e.g.,a salt of Li, Mg, or Zn). Non-limiting examples of an organic base thatcan be used in the Horner-Wadsworth-Emmons reaction includetrialkylamines (e.g., triethylamine or Hünig's base), DBU, and DBN.Non-limiting examples of Lewis acids that can be used in theHorner-Wadsworth-Emmons reaction include LiCl, Zn(OTf)₂, and MgCl₂.

The compound of formula (IIB) can be converted to a compound of formula(ID):

-   -   where    -   each P₃ is independently H or a hydroxyl protecting group, and        X₂ is oxo; or both P₃ groups and X₂, together with the atoms to        which each is attached, combine to form ketal; and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form an aminal or                1,3-oxazolidin-2-one-5-yl.

In a non-limiting example, the synthesis of the compound of formula (ID)from the compound of formula (IIB) can involve reacting the compound offormula (IIB) (e.g., the compound of formula (IIB), in which P₄ is aprotecting group, R₁ and R₂ form a bond, and R₃ is H) with a hydroxylprotecting group removing agent.

The compound of formula (ID) (in which X is O, P₁ and P₂ are H, and bothP₃ groups and X₂, together with the atoms to which each is attached,combine to form ketal) can be aminated to afford eribulin, as describedherein. Alternatively, the compound of formula (ID) (in which P₁ is H, Xand P₂ combine to form a masked amino, and both P₃ groups and X₂,together with the atoms to which each is attached, combine to formketal) can be reacted with an amino unmasking agent to afford eribulin,as described herein. Eribulin mesylate can be produced by salificationof eribulin, as described herein.

The compound of formula (IIA) can be prepared from a compound of formula(IIC):

-   -   where    -   (i) R₁ is H or a hydroxyl protecting group, and R₂ and R₃        combine to form a double bond;    -   or    -   (ii) R₁ and R₂ combine to form a bond, and R₃ is H;    -   R₄ is OH, and R₅ is H, or R₄ and R₅ combine to form a double        bond;    -   R₆ is —OP₅ or CH₂P(O)(OR₆)₂, where P₅ is an ether hydroxyl        protecting group, and each R₆ is independently optionally        substituted alkyl or optionally substituted aryl;    -   each P₃ is independently H or a hydroxyl protecting group, and        X₂ is oxo; or both P₃ groups and X₂, together with the atoms to        which each is attached, combine to form ketal;    -   P₄ is H or a hydroxyl protecting group; and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form an aminal or                1,3-oxazolidin-2-one-5-yl.

In some embodiments, the preparation of the compound of formula (IIA)from the compound of formula (IIC) can involve performinghydroboration/oxidation reaction on the compound of formula (IIC) (e.g.,the compound of formula (IIC), in which R₄ and R₅ combine to form adouble bond; R₁ and R₂ combine to form a bond; and R₃ is H). Thepreparation may involve subjecting the compound of formula (IIC) (e.g.,the compound of formula (IIC), in which R₆ is —OP₅) to a phospha-Claisenreaction with CH₃P(O)(OR₆)₂. Phospha-Claisen reaction conditions can bethose known in the art. In a non-limiting example, CH₃P(O)(OR₆)₂ can bedeprotonated (e.g., by a contact with a strong base) and subsequentlycontacted with the compound of formula (IIC). The preparation may alsoinvolve oxidizing the compound of formula (IIC) (e.g., the compound offormula (IIC), in which R₄ is OH, R₅ is H, and R₆ is CH₂P(O)(OR₆)₂),e.g., by contacting this product with an oxidizing agent capable ofoxidizing an alcohol to a carbonyl group.

The compound of formula (IIC) can be prepared from a compound of formula(VIIE), the compound of formula (VIIE) having the following structure:

-   -   where    -   Y₁ is SO₂R₁ and R₁ is optionally substituted non-enolizable        alkyl or optionally substituted aryl, or Y₁ is COOR₁, and R₁ is        optionally substituted alkyl, optionally substituted aryl, or        optionally substituted arylalkyl;    -   R₂ is

-   -    where X₁ is oxo, and R₄ is CHO; and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form an aminal or                1,3-oxazolidin-2-one-5-yl.

In a non-limiting example, the compound of formula (IIC) is prepared byreacting the compound of formula (VIIE) (e.g., the compound of formula(VIIE), in which R₂ is

and X₁ is oxo) with a compound of formula (IID), the compound of formula(IID) having the following structure:

-   -   where    -   R₄ is OH or OP₅, and R₅ is H, or R₄ and R₅ combine to form a        double bond;    -   each P₃, P₄, and P₅ is independently a hydroxyl protecting        group; and    -   Y is chloro, bromo, iodo, or trifluoromethanesulfonate.

The compound of formula (VIIE), in which X₁ is oxo, can be reacted withthe compound of formula (IID) under the Nozaki-Hiyama-Kishi reactionconditions, as described herein.

C.3-C.4 Bond-Forming Macrocyclization

The macrocyclization reaction of the invention can be a carbon-carbonbond-forming reaction (e.g., catalytic Ring-Closing olefin Metathesis(RCM)) that provides a C.3-C.4 bond in eribulin or a pharmaceuticallyacceptable salt thereof (e.g., eribulin mesylate). The general syntheticsequence including RCM that can be used to prepare eribulin or apharmaceutically acceptable salt thereof (e.g., a mesylate salt) isshown in FIG. 3. As shown in FIG. 3, the non-macrocyclic intermediate inthe synthesis of eribulin can be a compound of formula (IIIA):

-   -   where    -   (i) R₁ is H or a hydroxyl protecting group, and R₂ and R₃        combine to form a double bond;        -   or    -   (ii) R₁ and R₂ combine to form a bond, and R₃ is H;    -   X₃ is oxo, or X₃ combines with the carbon atom to which it is        attached to form a ketal, a thioketal, or —(CH(OP₅))—, wherein        P₅ is H or a hydroxyl protecting group;    -   each P₃ is independently H or a hydroxyl protecting group, and        X₂ is oxo; or both P₃ groups and X₂, together with the atoms to        which each is attached, combine to form ketal;    -   P₄ is H or a hydroxyl protecting group; and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or        -   P₁ and P₂, together with the atoms to which each is            attached, combine to form an aminal or            1,3-oxazolidin-2-one-5-yl.

An intermediate in the synthesis of eribulin can be a compound offormula (IIIB), which can be produced by reacting the compound offormula (IIIA) with an olefin metathesis catalyst (e.g., aruthenium-carbene complex). The compound of formula (IIIB) has thefollowing structure:

-   -   where all variables are as defined for formula (IIIA).

The catalysts that can be used to convert the compound of formula (IIIA)to the compound of formula (IIIB) can be those known in the art. Olefinmetathesis catalysts include Ru-carbene complexes (e.g., Grubbs andHoveyda-Grubbs catalysts).

The compound of formula (IIIB) can be converted to a compound of formula(ID), from which eribulin or eribulin mesylate can be prepared asdescribed herein. A non-limiting example of the preparation of thecompound of formula (ID) from the compound of formula (IIIB) is providedbelow.

The compound of formula (IIIB), in which X₃, together with the carbon towhich it is attached, forms —(CH(OP₅))—, where P₅ is H, can be oxidizedto afford the compound of formula (IIIB), in which X₃ is oxo.

Oxidation of the —(CH(OH))— in the compound of formula (IIIB) to givethe compound of formula (IIIB), in which X₃ is oxo, can be performedusing methods known in the art for oxidation of alcohols to carbonylgroups, e.g., by contacting the compound of formula (IIIB) with anoxidizing agent capable of converting an alcohol to a carbonyl group.

The compound of formula (IIIB) (e.g., the compound of formula (IIIB), inwhich X₃ is oxo, and P₁ is a hydroxyl protecting group) can be reactedwith a hydroxyl protecting group removing agent to afford a compound offormula (ID):

-   -   where    -   each P₃ is H, and X₂ is oxo; or both P₃ groups and X₂, together        with the atoms to which each is attached, combine to form ketal;        and        -   X is O, and P₁ and P₂ are H;        -   or        -   P₁ is H, and X and P₂ combine to form optionally masked            amino.

The conditions for the reaction used in preparing the compound offormula (ID) from the compound of formula (IIIB) can be those allowingfor isomerization of a β,γ-enone to an α,β-enone (e.g., including basicor acidic compounds). For example, a hydroxyl protecting group removingagent, such as a fluoride source (e.g., TBAF), can mediate theisomerization of a β,γ-enone to an α,β-enone, while unmasking hydroxylgroups protected with optionally substituted silyl groups.

The compound of formula (ID) (in which X is O, P₁ and P₂ are H, and bothP₃ groups and X₂, together with the atoms to which each is attached,combine to form ketal) can be aminated to afford eribulin, as describedherein. Alternatively, the compound of formula (ID) (in which P₁ is H, Xand P₂ combine to form a masked amino, and both P₃ groups and X₂,together with the atoms to which each is attached, combine to formketal) can be reacted with an amino unmasking agent to afford eribulin,as described herein. Eribulin mesylate can be produced by salificationof eribulin, as described herein.

The compound of formula (IIIA) can be prepared from a compound offormula (IIIC):

-   -   where    -   (i) R₁ is H or a hydroxyl protecting group, and R₂ and R₃        combine to form a double bond; or    -   (ii) R₁ and R₂ combine to form a bond, and R₃ is H;    -   X₃ is oxo and R₄ is H or OP₆, or X₃ and R₄ combine with the        carbon atom to which they are attached to form an acetal, a        thioacetal, or —CH₂OP₅; where P₅ is H or a hydroxyl protecting        group, and P₆ is an ether hydroxyl protecting group;    -   each P₃ is independently H or a hydroxyl protecting group, and        X₂ is oxo; or both P₃ groups and X₂, together with the atoms to        which each is attached, combine to form ketal;    -   P₄ is H or a hydroxyl protecting group; and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or        -   P₁ and P₂, together with the atoms to which each is            attached, combine to form an aminal or            1,3-oxazolidin-2-one-5-yl.

In some embodiments, the preparation of the compound of formula (IIIA)from the compound of formula (IIIC) involves allylating the compound offormula (IIIC) (e.g., the compound of formula (IIIC), in which R₄ is H,and X₃ is oxo, or X₃ and R₄ combine with the carbon atom to which theyare attached to form a thioacetal). Allylation of the compound offormula (IIIC) can be performed using conditions known in the art. In anon-limiting example, when X₃ is oxo, and R₄ is H, allylation of thecompound of formula (IIIC) can be a nucleophilic allylation (e.g., bycontacting the compound of formula (IIIC) with a nucleophilic allylatingagent (e.g., allylboron reagent (e.g., allyl boronate or allyl borane),allylstannane, allyl Grignard reagent, allylsilane, or allyl indium).Alternatively, allylation of the compound of formula (IIIC) can beperformed using electrophilic allylation (e.g., when X₃ and R₄ combinewith the carbon to which they are attached to form a thioacetal). In anon-limiting examples of electrophilic allylation, the compound offormula (IIIC), in which X₃ and R₄ combine with the carbon to which theyare attached to form a thioacetal, can be contacted with a strong basefollowed by an allylic electrophile (e.g., allyl halide or allylsulfonate).

The preparation of the compound of formula (IIIA) from the compound offormula (IIIC) can also involve reducing the compound of formula (IIIC),in which X₃ is oxo and R₄ is OP₆, with a 1,2-reducing agent to afford acompound of formula (IIIC), in which X₃ is oxo or —(CH(OH))—, and R₄ isH. Formation of the compound of formula (IIIC), in which X₃ is oxo, andR₄ is H, can be direct (e.g., by treating with DIBAL at a temperaturebetween about −70° C. and about −80° C.) or indirect via the compound offormula (IIIC), in which X₃ combines with the carbon atom to which it isattached to form —(CH(OH))—, and R₄ is H. The indirect route to thecompound of formula (IIIC), in which X₃ is oxo, and R₄ is H, thusinvolves first reducing the compound of formula (IIIC), in which X₃ isoxo, and R₄ is OP₆, with a 1,2-reducing agent to give the compound offormula (IIIC), in which X₃ combines with the carbon atom to which it isattached to form —(CH(OH))—, and R₄ is H. The latter compound can bereacted with an oxidizing agent capable of oxidizing an alcohol to acarbonyl group to furnish the compound of formula (IIIC), in which X₃ isoxo, and R₄ is H.

Throughout the oxidation, reduction, and allylation reactions describedabove, the sensitive functional groups present in the compound offormula (IIIC) can be protected (e.g., R₁ and each P₃ is independently ahydroxyl protecting group) or can be present in an unreactive form(e.g., both P₃ groups and X₂, together with the atoms to which each isattached, combine to form ketal).

C.19-C.20 Bond-Forming Macrocyclization

The macrocyclization reaction of the invention can be a carbon-carbonbond-forming reaction (e.g., Nozaki-Hiyama-Kishi reaction (NHK)) thatprovides a C.19-C.20 bond in eribulin or a pharmaceutically acceptablesalt thereof (e.g., eribulin mesylate). The general synthesis sequenceincluding NHK that can be used to prepare eribulin or a pharmaceuticallyacceptable salt thereof (e.g., a mesylate salt) is shown in FIG. 4. Asshown in FIG. 4, the non-macrocyclic intermediate in the synthesis oferibulin can be a compound of formula (IVA):

-   -   where    -   Y is iodide, bromide, or trifluoromethanesulfonate;    -   a designates R stereogenic center, and Z is a sulfonate,        chloride, bromide, or iodide; or a designates S stereogenic        center, and Z is OR₁, wherein R₁ is a hydroxyl protecting group;    -   (i) R₂ is H or a hydroxyl protecting group, R₃ and R₄ combine to        form a double bond;    -   or    -   (ii) R₂ and R₃ combine to form a bond, and R₄ is H;    -   each P₃ is independently H or a hydroxyl protecting group, and        X₂ is oxo; or both P₃ groups and X₂, together with the atoms to        which each is attached, combine to form ketal; and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form an aminal or                1,3-oxazolidin-2-one-5-yl.

An intermediate in the synthesis of eribulin can be a compound offormula (IVB), which can be produced by subjecting the compound offormula (IVA) to Nozaki-Hiyama-Kishi reaction conditions (e.g., byreacting with a Cr(II) salt and a Ni(II) salt). The compound of formula(IVB) has the following structure:

-   -   where P₁, P₂, P₃, X, and X₂ are as defined for compound of        formula (IVB);        -   a designates R stereogenic center, b designates S            stereogenic center, Z is a sulfonate, chloride, bromide, or            iodide;        -   or        -   a designates S stereogenic center, b designates R            stereogenic center, and Z is OR₁, wherein R₁ is a hydroxyl            protecting group.

Nozaki-Hiyama-Kishi reaction conditions that may be used to prepare thecompound of formula (IVB) from the compound of formula (IVA) can bethose known in the art. Nozaki-Hiyama-Kishi reaction on the compound offormula (IVA) can include reacting the compound of formula (IVA) with aCr(II) salt and a Ni(II) salt. Ancillary ligands can be used incombination with the metal salts. In a non-limiting example, asubstituted 1,10-phenanthroline can be used in combination with a Ni(II)salt. Chiral ancillary ligands can be used to render the reactionstereoselective. In a non-limiting example, chiralN-(dihydrooxazolyl-phenyl)-sulfonamides can be used with a Cr(II) saltto control the stereochemistry of the carbonyl carbon, to which a vinylnucleophile is added in the course of Nozaki-Hiyama-Kishi reaction.

The compound of formula (IVB) can be converted to a compound of formula(ID), from which eribulin or erinulin mesylate can be prepared, asdescribed herein. A non-limiting exemplary reaction sequence from thecompound of formula (IVB) to the compound of formula (ID) is providedbelow.

The compound of formula (IVB) can be converted to a compound of formula(ID) directly or via an intermediate of formula (IVC). Thus, thecompound of formula (IVB), in which Z is an ester, a designates Sstereogenic center, b designates R stereogenic center, can be convertedto the compound of formula (IVC), e.g., by reacting with a sulfonylelectrophile, such as a sulfonyl chloride or a sulfonyl anhydride.

-   -   where    -   a designates S stereogenic center;    -   b designates R stereogenic center;    -   Z is an ester;    -   (i) R₂ is H or a hydroxyl protecting group, R₃ and R₄ combine to        form a double bond;    -   or    -   (ii) R₂ and R₃ combine to form a bond, and R₄ is H;    -   R₅ is sulfonyl;    -   each P₃ is independently a hydroxyl protecting group, and X₂ is        oxo; or both P₃ groups and X₂, together with the atoms to which        each is attached, combine to form ketal;    -   and        -   X is O, and            -   each of P₁ and P₂ is independently a hydroxyl protecting                group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   P₁ is a hydroxyl protecting group, and X and P₂ combine to            form optionally masked amino.

The preparation of the compound of formula (ID) from the compound offormula (IVC) can involve reacting the compound of formula (IVC) with aC₁₋₆ alkoxide. The compound of formula (ID) has the following structure:

-   -   where    -   each P₃ is independently H or a hydroxyl protecting group, and        X₂ is oxo; or both P₃ groups and X₂, together with the atoms to        which each is attached, combine to form ketal; and        -   X is O, and            -   each of P₁ and P₂ is independently a hydroxyl protecting                group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   P₁ is a hydroxyl protecting group, and X and P₂ combine to            form optionally masked amino.

The compound of formula (IVB) (in which Z is a sulfonate, chloride,bromide, or iodide, a designates R stereogenic center, b designates Sstereogenic center, R₂ and R₃ combine to form a bond, and R₄ is H) canbe converted to the compound of formula (ID) directly, e.g., uponisolation from the Nozaki-Hiyama-Kishi reaction mixture (e.g., bytreatment with a base) or by contacting a mixture containing the productof the Nozaki-Hiyama-Kishi reaction with silica gel.

The compound of formula (ID) (e.g., the compound of formula (ID) inwhich P₁ is a hydroxyl protecting group) can be reacted with a hydroxylprotecting group removing agent to afford:

-   -   where    -   each P₃ is independently H or a hydroxyl protecting group, and        X₂ is oxo; or both P₃ groups and X₂, together with the atoms to        which each is attached, combine to form ketal; and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form an aminal or                1,3-oxazolidin-2-one-5-yl.

The compound of formula (ID) (in which X is O, P₁ and P₂ are H, and bothP₃ groups and X₂, together with the atoms to which each is attached,combine to form ketal) can be aminated to afford eribulin, as describedherein. Alternatively, the compound of formula (ID) (in which P₁ is H, Xand P₂ combine to form a masked amino, and both P₃ groups and X₂,together with the atoms to which each is attached, combine to formketal) can be reacted with an amino unmasking agent to afford eribulin,as described herein. Eribulin mesylate can be produced by salificationof eribulin, as described herein.

The compound of formula (IVA) can be prepared from the compound offormula (IVD):

-   -   where    -   Y is iodide, bromide, or trifluoromethanesulfonate;    -   Y₁ is H, COOR₆, or SO₂R₆, where, when Y₁ is COOR₆, R₆ is        optionally substituted alkyl, optionally substituted aryl, or        optionally substituted arylalkyl, and, when Y₁ is SO₂R₆, R₆ is        optionally substituted aryl or optionally substituted        non-enolizable alkyl;    -   Z is an ester, a sulfonate, chloride, bromide, or iodide;    -   (i) R₂ is H or a hydroxyl protecting group, R₃ and R₄ combine to        form a double bond;    -   or    -   (ii) R₂ and R₃ combine to form a bond, and R₄ is H;    -   each P₃ is independently H or a hydroxyl protecting group, and        X₂ is oxo; or both P₃ groups and X₂, together with the atoms to        which each is attached, combine to form ketal;    -   X₃ is oxo, or X₃ combines with the carbon atom to which it is        attached to form —(CH(OH))—; and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form an aminal or                1,3-oxazolidin-2-one-5-yl.

In some embodiments, the preparation of the compound of formula (IVA)involves oxidizing the compound of formula (IVD), in which X₃ is—(CH(OH))—, and/or P₄ is H, e.g., by reacting with an oxidizing agentcapable of oxidizing an alcohol to a carbonyl group. The preparation ofthe compound of formula (IVA) can also involve performing adecarboxylation or desulfonylation reaction on the compound of formula(IVA), in which Y₁ is COOR₆ (decarboxylation) or SO₂R₆(desulfonylation).

In certain embodiments, the compound of formula (IVD) can be preparedfrom a compound of formula (IVE) and the compound of formula (VIIE):

-   -   or a salt thereof,    -   where all variables are as defined in formula (IVD).

The compound of formula (IVE) can have the following structure:

-   -   where    -   (a1) R₇ and R₈ combine to form a bond, and R₉ is H;    -   or    -   (a2) R₇ is H or a hydroxyl protecting group, and R₈ and R₉        combine to form a double bond;    -   X₃ is oxo, and R₁₀ is H or —OP₅, where P₅ is H or an ether        hydroxyl protecting group; and    -   the remaining variables are as defined in formula (IVD).

In particular embodiments, the compound of formula (IVD) is prepared byreacting the compound of formula (IVE) (e.g., the compound of formula(IVE), in which X is oxo) with the compound of formula (VIIE) which waspretreated with a strong base.

C.0-C.1 Bond-Forming Macrocyclization

The macrocyclization reaction of the invention can be a carbon-carbonbond-forming reaction (e.g., Dieckmann reaction) that provides a C.0-C.1bond in eribulin or a pharmaceutically acceptable salt thereof (e.g.,eribulin mesylate). The general synthetic sequence including theDieckmann reaction that can be used to prepare eribulin or apharmaceutically acceptable salt thereof (e.g., a mesylate salt) isshown in FIG. 5. As shown in FIG. 5, the non-macrocyclic intermediate inthe synthesis of eribulin can be:

-   -   where    -   Y is SO₂R₁ or COOR₁, where, when Y is SO₂R₁, R₁ is optionally        substituted aryl or optionally substituted non-enolizable alkyl,        and when Y is COOR₁, R₁ is optionally substituted alkyl,        optionally substituted aryl, or optionally substituted        arylalkyl;    -   each P₃ is independently H or a hydroxyl protecting group, and        X₂ is oxo, or both P₃ groups and X₂, together with the atoms to        which each is attached, combine to form ketal;    -   R₂ is optionally substituted alkyl, optionally substituted        arylalkyl, or optionally substituted aryl; and    -   X is O, and        -   each of P₁ and P₂ is independently a hydroxyl protecting            group,        -   or        -   P₁ and P₂, together with the atoms to which each is            attached, combine to form a cyclic protected diol;    -   or    -   X is N, and        -   P₁ is H or a hydroxyl protecting group, and X and P₂ combine            to form optionally masked amino;        -   or        -   P₁ and P₂, together with the atoms to which each is            attached, combine to form an aminal or            1,3-oxazolidin-2-one-5-yl.

An intermediate in the synthesis of eribulin can be a compound offormula (VB), which can be produced from the compound of formula (VA)using Dieckmann reaction. The compound of formula (VB) has the followingstructure:

-   -   where P₁, P₂, P₃, X, X₂, and Y are as defined for compound of        formula (VA); and    -   (i) R₃ is H, R₄ is optionally substituted C₁₋₆ alkyl ether, and        R₅ is H;    -   (ii) R₅ is H, and R₃ and R₄ combine to form a double bond;    -   or    -   (iii) R₃ is H, and R₄ and R₅ combine to form a bond

The reaction conditions that can be used to convert the compound offormula (VA) into the compound of formula (VB) include those known inthe art for the Dieckmann reaction or Claisen condensation. Inparticular, the compound of formula (VA) can be contacted with a strongbase (e.g., a C₄₋₆ alkoxide) to afford the compound of formula (VB). Thecompound of formula (VB)(i) or (VB)(ii) can be converted to the compoundof formula (VB)(iii) prior to the next step by contacting the compoundof formula (IIB)(i) or (VB)(ii) with aqueous bicarbonate (e.g., during awork up of the Dieckmann reaction mixture) or with silica gel (e.g., bypurification of the compound of formula (VB) by silica gelchromatography).

The compound of formula (VB) can be converted to the compound of formula(ID), from which eribulin or eribulin mesylate can be produced asdescribed herein. For example, the reaction sequence from the compoundof formula (VB) to the compound of formula (ID) can include (i) adesulfonylation or a decarboxylation reaction and (ii) reactions withhydroxyl protecting group removing agent or an amino unmasking agent.The conditions for the decarboxylation reaction can be those known inthe art, e.g., Krapcho decarboxylation or a sequence includingdeprotection (converting R₁ to H) and protodecarboxylation. Theconditions for the desulfonylation reaction can be those known in theart. For example, the desulfonylation reaction can include contactingthe compound of formula (IIB), in which Y is SO₂R₁, with anelectron-transferring reducing agent (e.g., SmI₂; Cr(III) salt andMn(0); or Mg(0)). For exemplary desulfonylation conditions, see WO2009/064029.

The compound of formula (ID) (e.g., the compound of formula (ID) inwhich P₁ is a hydroxyl protecting group) can be reacted with a hydroxylprotecting group removing agent to afford:

-   -   where    -   both P₃ groups and X₂, together with the atoms to which each is        attached, combine to form ketal; and        -   X is O, and each of P₁ and P₂ is H,        -   or            P₁ is H, and X and P₂ combine to form optionally masked            amino.

The compound of formula (ID) (in which X is O, P₁ and P₂ are H, and bothP₃ groups and X₂, together with the atoms to which each is attached,combine to form ketal) can be aminated to afford eribulin, as describedherein. Alternatively, the compound of formula (ID) (in which P₁ is H, Xand P₂ combine to form a masked amino, and both P₃ groups and X₂,together with the atoms to which each is attached, combine to formketal) can be reacted with an amino unmasking agent to afford eribulin,as described herein. Eribulin mesylate can be produced by salificationof eribulin, as described herein.

The compound of formula (VA) can be prepared from the compound offormula (VIIE):

-   -   where    -   Y is SO₂R₁ or COOR₁, where, when Y is SO₂R₁, R₁ is optionally        substituted aryl or optionally substituted non-enolizable alkyl,        and when Y is COOR₁, R₁ is optionally substituted alkyl,        optionally substituted aryl, or optionally substituted        arylalkyl;    -   P₃ is H or a hydroxyl protecting group; and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or        -   P₁ and P₂, together with the atoms to which each is            attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form an aminal or                1,3-oxazolidin-2-one-5-yl.

The preparation of the compound of formula (VA) from the compound offormula (VIIE) can involve oxidizing the compound of formula (VIIE), inwhich P₃ is H, and subjecting the product to the Nozaki-Hiyama-Kishireaction with a compound of formula (VC):

-   -   where    -   R₂ is optionally substituted alkyl, optionally substituted        arylalkyl, or optionally substituted aryl;    -   Y₁ is chloro, bromo, iodo, or trifluoromethanesulfonate; and    -   each P₃ and P₄ is independently a hydroxyl protecting group.

Further reaction with a hydroxyl protecting group removing agent and areaction with a Brønsted acid can provide the compound of formula (VA).

C.26-C.27 Bond-Forming Macrocyclization

The macrocyclization reaction of the invention can be a carbon-carbonbond-forming reaction (e.g., Nozaki-Hiyama-Kishi reaction (NHK)) thatprovides a C.26-C.27 bond in eribulin or a pharmaceutically acceptablesalt thereof (e.g., eribulin mesylate). The general synthesis sequenceincluding NHK that can be used to prepare eribulin or a pharmaceuticallyacceptable salt thereof (e.g., a mesylate salt) is shown in FIG. 6. Asshown in FIG. 6, the non-macrocyclic intermediate in the synthesis oferibulin can be a compound of formula (VIA):

-   -   where    -   Y is iodide, bromide, or trifluoromethanesulfonate;    -   (a1) R₃ is H or a hydroxyl protecting group, R₄ and R₅ combine        to form a double bond, each P₃ is independently H or a hydroxyl        protecting group, and X₂, together with the carbon to which it        is attached, forms a carbonyl or —(CH(OR₆))—, where R₆ is H or a        hydroxyl protecting group;    -   or    -   (a2) R₃ and R₄ combine to form a bond, R₅ is H, and        -   each P₃ is independently H or a hydroxyl protecting group,            and X₂, together with the carbon to which it is attached,            forms a carbonyl or —(CH(OR₆))—;        -   or        -   both P₃ groups and X₂, together with the atoms to which each            is attached, combine to form ketal;    -   (b1) Z is chloride, bromide, or iodide, and R₁ and R₂ combine to        form a bond;    -   or    -   (b2) Z and R₂ combine to form a double bond, and R₁ is H or a        hydroxyl protecting group;    -   and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form an aminal or                1,3-oxazolidin-2-one-5-yl.

An intermediate in the synthesis of eribulin can be a compound offormula (VIB), which can be produced by subjecting the compound offormula (VIA) to Nozaki-Hiyama-Kishi reaction conditions (e.g., byreacting with a Cr(II) salt and a Ni(II) salt). The compound of formula(VIB) has the following structure:

-   -   where all variables are as defined for compound of formula        (VIA); and    -   P₄ is H or a hydroxyl protecting group.

Nozaki-Hiyama-Kishi reaction conditions are as described above.

The compound of formula (VIC) can be prepared from the compound offormula (VIB):

-   -   where all variables are as defined for compound of formula        (VIB).

The synthesis of the compound of formula (VIC) can involve Vasellafragmentation, reaction(s) with one or more hydroxyl protecting agents,a nucleophilic cyclization reaction, and oxidation reactions, e.g.,before or after the NHK step (i.e., the reaction affording the compoundof formula (VIB)).

The compound of formula (VIC) can be converted to the compound offormula (ID), from which eribulin or eribulin mesylate can be preparedas described herein. In a non-limiting example, the compound of formula(VIC) (e.g., the compound of formula (VIC) in which each of P₁, P₂, P₃,and R₃ is a hydroxyl protecting group, X₂ is oxo, and R₄ and R₅ combineto form a double bond) can be converted to a compound of formula (ID)through a synthesis involving reacting the compound of formula (VIC)with a hydroxyl protecting group removing agent. The synthesis mayfurther involve a reaction with a Brønsted acid (e.g., a Brønsted acidhaving a pKa of 5±3) after the reaction of the compound of formula (VIC)with a hydroxyl protecting group removing agent.

The compound of formula (ID) (e.g., the compound of formula (ID) inwhich P₁ is a hydroxyl protecting group) can be reacted with a hydroxylprotecting group removing agent:

-   -   where    -   both P₃ groups and X₂, together with the atoms to which each is        attached, combine to form ketal; and        -   X is O, and each of P₁ and P₂ is H,        -   or        -   P₁ is H, and X and P₂ combine to form optionally masked            amino.

The compound of formula (ID) (in which X is O and P₁ and P₂ are H) canbe aminated to afford eribulin, as described herein. Alternatively, thecompound of formula (ID) (in which P₁ is H and X and P₂ combine to forma masked amino) can be reacted with an amino unmasking agent to afforderibulin, as described herein. Eribulin mesylate can be produced bysalification of eribulin, as described herein.

The compound of formula (VIA) can be prepared from the compound offormula (VID):

-   -   where    -   Y is iodide, bromide, or trifluoromethanesulfonate;    -   Y₁ is H, SO₂R₇, or COOR₇, where, when Y₁ is COOR₇, R₇ is        optionally substituted alkyl, optionally substituted aryl, or        optionally substituted arylalkyl, and, when Y₁ is SO₂R₇, R₇ is        optionally substituted aryl or optionally substituted        non-enolizable alkyl;    -   X₃ is oxo, or X₃ combines with the carbon to which it is        attached to form —(CH(OR₆))—;    -   P₅ is H or a hydroxyl protecting group;    -   (a1) R₃ is H or a hydroxyl protecting group, R₄ and R₅ combine        to form a double bond, each P₃ is independently H or a hydroxyl        protecting group, and X₂, together with the carbon to which it        is attached, forms a carbonyl or —(CH(OR₆))—;    -   or    -   (a2) R₃ and R₄ combine to form a bond, R₅ is H, and        -   each P₃ is independently H or a hydroxyl protecting group,            and X₂, together with the carbon to which it is attached,            forms a carbonyl or —(CH(OR₆))—;        -   or        -   both P₃ groups and X₂, together with the atoms to which each            is attached, combine to form ketal;    -   (b1) Z is chloride, bromide, or iodide, and R₁ and R₂ combine to        form a bond;    -   or    -   (b2) Z and R₂ combine to form a double bond, and R₁ is a        hydroxyl protecting group;    -   and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form an aminal or                1,3-oxazolidin-2-one-5-yl;    -   where each R₆ is independently H or a hydroxyl protecting group.

The preparation of the compound of formula (VIA) can involve oxidizingthe compound of formula (VID) (e.g., the compound of formula (VID), inwhich P₅ is H or a hydroxyl protecting group, and/or X₃ combines withthe carbon to which it is attached to form —(CH(OR₆))—), e.g., byreacting with an oxidizing agent capable of oxidizing hydroxyl to acarbonyl group. The mixture containing the oxidizing agent can also actas a hydroxyl protecting removing agent. The preparation may furtherinvolve a desulfonylation reaction (when Y₁ is COOR₇) or adesulfonylation (when Y₁ is SO₂R₇), as described herein.

The compound of formula (VID) can be formed by reacting the compound offormula (VIE) with the compound of formula (VIF). The compound offormula (VIE) can have the following structure:

-   -   where    -   R₈ is H or —OR₉, where R₉ is H or an ether hydroxyl protecting        group; and    -   the remaining variables are as defined in formula (VID).

The compound of formula (VIF) can have the following structure

-   -   where all variables are as defined in formula (VID).        Allene-Prins Reaction in the Preparation of C.20-C.35,        C.16-C.35, and C.14-C35 Fragments of Eribulin

The invention further features a method of preparing a fragment oferibulin (e.g., C.20-C.35, C.16-C.35, and C.14-C35 fragments), which canbe an intermediate in the synthesis of eribulin or a pharmaceuticallyacceptable salt thereof (e.g., eribulin mesylate). The advantages of theprocess relative to the current synthesis of C.14--C.35, C.16-C.35, andC.20-C.35 fragments of eribulin include non-metal mediated assembly thatdoes not employ a C.23 leaving group. Additionally, the process obviatesthe need for a chiral ligand. The method involves performing anallene-Prins reaction on a compound of formula (VIIA), a compound offormula (VIIB), and R₃OH to afford the intermediate in the synthesis oferibulin,

where R₃ is an optionally substituted acyl;

where the compound of formula (VIIA) has the following structure:

where

Y₁ is SO₂R₁ or COOR₁, and R₁ is optionally substituted alkyl, optionallysubstituted aryl, or optionally substituted arylalkyl;

X₁ is O, or X₁, together with the carbon to which the X₁ groups areattached, forms a cyclic acetal;

-   -   X is O, and        -   each of P₁ and P₂ is independently H or a hydroxyl            protecting group,        -   or        -   P₁ and P₂, together with the atoms to which each is            attached, combine to form a cyclic protected diol;    -   or    -   X is N, and        -   P₁ is H or a hydroxyl protecting group, and X and P₂ combine            to form optionally masked amino;        -   or        -   P₁ and P₂, together with the atoms to which each is            attached, combine to form an aminal or            1,3-oxazolidin-2-one-5-yl; and

where the compound of formula (VIIB) has the following structure:

where

R₂ is —CH₂—OP₃, —CH═CH₂,

where

-   -   P₃ is H or a hydroxyl protecting group; each P₄ is independently        a hydroxyl protecting group, or both P₄ groups, together with        the atoms to which each is attached, combine to form a    -   cyclic protected diol; and R₄ is is H or —CH₂X₂CH₂CH═CH₂, where        X₂ is O, —CH₂—, or NP₅, where P₅ is sulfonyl;

and where the intermediate in the synthesis of eribulin is a compound offormula (VIIC):

The reaction conditions that can be used to prepare the compound offormula (VIIC) using allene-Prins reaction are those known in the artfor Prins reaction and can include reacting the compound of formula(VIIA), the compound of formula (VIIB), and R₃OH with a Lewis acid(e.g., boron trifluoride or a solvate thereof).

The compound of formula (VIIC) can be subjected to allylic reducingconditions to afford a compound of formula (VIID):

-   -   Y₁ is SO₂R₁ or COOR₁, and R₁ is optionally substituted alkyl,        optionally substituted aryl, or optionally substituted        arylalkyl;    -   R₂ is —CH₂—OP₃, —CH═CH₂,

-   -   -   where        -   P₃ is H or a hydroxyl protecting group; each P₄ is            independently a hydroxyl protecting group, or both P₄            groups, together with the atoms to which each is attached,            combine to form a cyclic protected diol; and R₄ is H or            —CH₂X₂CH₂CH═CH₂, where X₂ is O, —CH₂—, or NP₅, where P₅ is            sulfonyl;        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;            -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form an aminal or                1,3-oxazolidin-2-one-5-yl.

The compound of formula (VIIB) can be prepared from the compound offormula (VIIF):

-   -   where    -   Y is chloro, bromo, iodo, or sulfonate; and    -   R₂ is —CH₂—OP₃, —CH═CH₂,

-   -   -   where        -   P₃ is a hydroxyl protecting group; each P₄ is independently            a hydroxyl protecting group, or both P₄ groups, together            with the atoms to which each is attached, combine to form a            cyclic protected diol; and R₄ is H or —CH₂X₂CH₂CH═CH₂, where            X₂ is O, —CH₂—, or NP₅, where P₅ is sulfonyl.

The compound of formula (VIIF) can be reacted with a Pd(0) complex,which can be prepared in situ, and a base to afford the compound offormula (VIIB). Alternatively, the compound of formula (VIIB) can bereacted with a base directly (e.g., N-methylimidazole) to afford thecompound of formula (VIIB).

The compound of formula (VIIB) can be prepared from a compound offormula (VIIG):

-   -   where    -   Y is chloro, bromo, iodo, or sulfonate; and    -   R₂ is —CH₂—OP₃, —CH═CH₂,

-   -   -   where        -   P₃ is a hydroxyl protecting group; each P₄ is independently            a hydroxyl protecting group, or both P₄ groups, together            with the atoms to which each is attached, combine to form a            cyclic protected diol; and R₄ is H or —CH₂X₂CH₂CH═CH₂, where            X₂ is O, —CH₂—, or NP₅, where P₅ is sulfonyl.

The compound of formula (VIIG) can be reacted with a methylcuprate (I)salt (e.g., lithium methyl-cyanocuprate) to form the compound of formula(VIIB).

The compound of formula (VIIB) can be prepared from a compound offormula (VIIH):

-   -   where    -   R₂ is —CH₂—OP₃, —CH═CH₂,

-   -   -   where        -   P₃ is a hydroxyl protecting group; each P₄ is independently            a hydroxyl protecting group, or both P₄ groups, together            with the atoms to which each is attached, combine to form a            cyclic protected diol; and R₄ is H or —CH₂X₂CH₂CH═CH₂, where            X₂ is O, —CH₂—, or NP₅, where P₅ is sulfonyl.

The compound of formula (VIIH) can be reacted with a sulfonyl hydrazide(e.g., mesitylsulfonyl hydrazide) and a base (e.g., an organic basehaving a pKa from 10 to 14).

C.1-C.15 Fragment

The invention also features a C.1-C.15 fragment of eribulin, which canbe used in the synthesis of eribulin. The C.1-C.15 fragment can beprepared from the waste stream in the synthesis or eribulin disclosed inWO 2005/118565 (see preparation of the intermediate ER-806055). TheC.1-C.15 fragment can be a compound of formula (VIIIL):

-   -   where    -   R₁ is H or —CH₂OP₄;    -   X₂ is oxo, or X₂, together with the carbon to which it is        attached, forms a ketal or —(CH(OP₆))—;    -   each of P₁ and P₄, when present, is independently H or a        hydroxyl protecting group, or P₁ and P₄, when present, together        with the atoms to which each is attached, combine to form a        cyclic protected diol; and    -   each of P₂, P₅, and P₆ is independently H or a hydroxyl        protecting group.

The method of preparing the C.1-C.15 fragment can involve:

-   -   (A) cleaving the double bond in a compound of formula (VIIIA) to        afford a compound of formula (VIIIB), the compound of formula        (VIIIA) having the structure:

-   -   where        -   X₁ is oxo, or X₁, together with the carbon atom to which it            is attached, forms a ketal or —(CH(OP₃))—, wherein P₃ is H            or a hydroxyl protecting group;        -   R₁ is H or —CH₂OP₄;        -   each of P₁, P₂, and P₄ is independently a hydroxyl            protecting group, or        -   P₁ and P₄, together with the atoms to which each is            attached, combine to form a cyclic protected diol; and    -   the compound of formula (VIIIB) having the structure:

-   -   (B) reacting the compound of formula (VIIIB) with a compound of        formula (VIIIB-a) to afford a compound of formula (VIIIC):

-   -   where R₂ is H or —CH₂CH₂OP₅, and P₅ is a hydroxyl protecting        group;    -   and the compound of formula (VIIIB-a) has the following        structure:

-   -   (C) reacting the compound of formula (VIIIC) with a dehydrating        agent to afford a compound of formula (VIIID):

-   -   (D) reacting the compound of formula (VIIID) with a        dihydroxylating agent to afford a compound of formula (VIIIE):

-   -   (E) preparing a compound of formula (VIIIF) through a reaction        sequence comprising reacting the compound of formula (VIIIE)        with N-bromosuccinimide to afford a first intermediate, and (a),        when R₂ is —CH₂CH₂OP₅, contacting said first intermediate with a        reducing agent (e.g., a hydrosilane and a Brønsted or Lewis        acid), or (b), when R₂ is H, reacting said first intermediate        with an acylating agent (e.g., carboxylic acid anhydride) to        afford a second intermediate, and allylating said second        intermediate to afford a compound of formula (VIIIF):

-   -   where Z is an ester or —OP₇, where P₇ is H or a hydroxyl        protecting group, and R₃ is —CH₂CH₂OP₅ or —CH₂CH═CH₂;    -   (F) reacting the compound of formula (VIIIF) with a 1,4-reducing        agent to afford a compound of formula (VIIIG):

-   -   (G) forming a compound of formula (VIIIH) through a reaction        sequence comprising reacting the compound of formula (VIIIG)        with a Brønsted acid and Y—H, wherein Y is optionally        substituted C₁₋₆ alkyl, the compound of formula (VIIIH) having        the following structure:

-   -   where Y is optionally substituted C₁₋₆ alkyl ether; R₃ is        —CH₂CH₂OP₅; X₂ is oxo, or X₂, together with the carbon to which        it is attached, forms a ketal or —(CH(OP₆))—, where P₆ is a        hydroxyl protecting group;    -   (H) replacing P₂ in the compound of formula (VIIIH) with        —Si(R₄)₂H to afford a compound of formula (VIIIJ):

-   -   where each R₄ is independently optionally substituted alkyl,        optionally substituted aryl, or optionally substituted        arylalkyl;    -   (I) reacting the compound of formula (VIIIJ) with a Lewis acid        to afford a compound of formula (VIIIK):

-   -   where Y₂ is fluoro, chloro, or bromo;    -   and    -   (J) reacting the compound of formula (VIIIK) with a hydroxyl        protecting group removing agent and then reacting with a        hydroxyl protecting agent to afford a compound of formula        (VIIIL):

-   -   where P₂ is a hydroxyl protecting group.        Compounds

The present invention also provides compounds that can be used in thesynthesis of eribulin or a pharmaceutically acceptable salt thereof(e.g., eribulin mesylate), e.g., the compounds of formula (IA), (IB),(IC), (ID), (IE), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), (IVA),(IVB), (IVC), (IVD), (VA), (VB), (VIA), (VIB), (VIC), (VID), (VIIB),(VIIC), (VIIF), (VIIG), (VIIH), or (VIIIL), or a salt thereof. Thepresent invention also includes a compound of formula (VIIE):

-   -   or a salt thereof,    -   where    -   Y₁ is SO₂R₁ or COOR₁, and R₁ is optionally substituted alkyl,        optionally substituted aryl, or optionally substituted        arylalkyl;    -   R₂ is —CH₂—OP₃, —CH═CH₂,

-   -   -   where X₁ is oxo, or X₁ combines with the carbon atom to            which it is attached to form —(CH(OP₃))—; each P₃ is            independently H or a hydroxyl protecting group; each P₄ is            independently H or a hydroxyl protecting group, or both P₄            groups, together with the atoms to which each is attached,            combine to form a cyclic protected diol; R₄ is H, CHO, or            —CH₂X₂CH₂CH═CH₂, where X₂ is O, —CH₂—, or NP₅, where P₅ is            sulfonyl; and

    -   X is N, and P₁ is H or a hydroxyl protecting group, and X and P₂        combine to form optionally masked amino; or P₁ and P₂, together        with the atoms to which each is attached, combine to form an        aminal or 1,3-oxazolidin-2-one-5-yl.

The present invention includes a compound of formula (IVE):

-   -   where    -   Y is iodide, bromide, or trifluoromethanesulfonate;    -   Z is an ester, a sulfonate, chloride, bromide, or iodide;    -   each P₃ is independently H or a hydroxyl protecting group, and        X₂ is oxo; or both P₃ groups and X₂, together with the atoms to        which each is attached, combine to form ketal;    -   (a1) R₂ is H or a hydroxyl protecting group, R₃ and R₄ combine        to form a double bond;    -   or    -   (a2) R₂ and R₃ combine to form a bond, and R₄ is H;    -   (b1) R₇ and R₈ combine to form a bond, and R₉ is H;    -   or    -   (b2) R₇ is H or a hydroxyl protecting group, and R₈ and R₉        combine to form a double bond; and    -   (c1) X₃ is oxo, and R₁₀ is H or —OP₅, where P₅ is H or an ether        hydroxyl protecting group;    -   or    -   (c2) X₃ and R₁₀ combine with the carbon atom to which they are        attached to form an acetal or —CH₂OP₆, where P₆ is H or a        hydroxyl protecting group.

The present invention includes a compound of formula (VIE):

-   -   where    -   Y is iodide, bromide, or trifluoromethanesulfonate;    -   (a1) R₃ is H or a hydroxyl protecting group, R₄ and R₅ combine        to form a double bond, each P₃ is independently H or a hydroxyl        protecting group, and X₂, together with the carbon to which it        is attached, forms a carbonyl or —(CH(OR₆))—;    -   or    -   (a2) R₃ and R₄ combine to form a bond, R₅ is H, and        -   each P₃ is independently H or a hydroxyl protecting group,            and X₂, together with the carbon to which it is attached,            forms a carbonyl or —(CH(OR₆))—;        -   or        -   both P₃ groups and X₂, together with the atoms to which each            is attached, combine to form ketal;    -   (b1) Z is chloride, bromide, or iodide, and R₁ and R₂ combine to        form a bond;    -   or    -   (b2) Z and R₂ combine to form a double bond, and R₁ is H or a        hydroxyl protecting group;    -   (c1) X₃ is oxo, and R₈ is H or —OR₉, where R₉ is H or a hydroxyl        protecting group;    -   (c2) X₃ and R₈ combine with the carbon to which they are        attached to form an acetal;    -   (c3) X₃ and R₈ combine with the carbon to which they are        attached to form —CH₂OR₆;    -   or    -   (c4) X₃ and R₈ combine with the carbon to which they are        attached to form —CN;    -   and        -   X is O, and            -   each of P₁ and P₂ is independently H or a hydroxyl                protecting group,            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form a cyclic protected diol;        -   or        -   X is N, and            -   P₁ is H or a hydroxyl protecting group, and X and P₂                combine to form optionally masked amino;            -   or            -   P₁ and P₂, together with the atoms to which each is                attached, combine to form an aminal or                1,3-oxazolidin-2-one-5-yl;    -   where each R₆ is independently H or a hydroxyl protecting group.        Amination

Amination conditions can be those known in the art. In a non-limitingexample, C.35 hydroxyl in the compound of formula (IC) (e.g., a compoundof formula (IC) in which each of P₁ and P₂ is H and X is O) can besulfonylated (e.g., by a reaction with a sulfonyl anhydride or asulfonyl chloride) and reacted with a nitrogen source (e.g., ammonia,azide, sulfamic acid, urea (H₂NCONH₂), or thiourea (H₂NCSNH₂)) to afforderibulin or a pharmaceutically acceptable salt thereof upon optionalunmasking of the amino group (if the nitrogen source was azide, urea, orthiourea). In another non-limiting example, C.35 hydroxyl in thecompound of formula (IC) (e.g., a compound of formula (IC) in which P₁is a hydroxyl protecting group, and P₂ is H and X is O) can behalogenated (e.g., by Appel reaction or a reaction with thionylchloride, sulfuryl chloride, phosphorus(III) chloride, or phosphorus(V)oxychloride) and reacted with a nitrogen source (e.g., ammonia, azide,sulfamic acid, a phthalimide salt, urea (H₂NCONH₂), or thiourea(H₂NCSNH₂)) to afford eribulin or a pharmaceutically acceptable saltthereof upon optional unmasking of the amino group (if the nitrogensource was azide, a phthalimide salt, urea, or thiourea). In yet anothernon-limiting example, C.35 hydroxyl in the compound of formula (IC)(e.g., a compound of formula (IC) in which P₁ is a hydroxyl protectinggroup, and X and P₂ combine to form optionally masked amino) can bereacted with a hydroxyl protecting group removing agent to afforderibulin (when X and P₂ combine to form unmasked amino) or, when X andP₂ combine to form a masked amino, either before or after the treatmentwith the hydroxyl protecting group removing agent, the compound offormula (IC) can be reacted with an amino unmasking agent to afforderibulin. Amino unmasking agents are further described herein. Theamination reaction can provide a pharmaceutically acceptable salt oferibulin directly. Alternatively, the amination reaction can provideeribulin in a free base form. A pharmaceutically acceptable salt oferibulin can be prepared from eribulin through a salification reactionas described herein.

Salification

Salification reaction conditions are known in the art. Salification oferibulin can afford a pharmaceutically acceptable salt of eribulin(e.g., eribulin mesylate). In particular, salification reaction caninvolve contacting eribulin with a Brønsted acid (e.g., apharmaceutically acceptable Brønsted acid (e.g., methanesulfonic acid))to afford a pharmaceutically acceptable salt of eribulin (e.g., Handbookof Pharmaceutical Salts: Properties, Selection and Use, ed.: Stahl andWermuth, Wiley-VCH/VHCA, Weinheim/Zurich, 2002). Pharmaceuticallyacceptable salts of eribulin, e.g., eribulin mesylate, can be formed bymethods known in the art, e.g., in situ during the final isolation andpurification of the compound or separately by reacting the free basegroup with a suitable organic acid. In one example, eribulin is treatedwith a solution of MsOH and NH₄OH in water and acetonitrile. The mixtureis concentrated. The residue is dissolved in DCM-pentane, and thesolution is added to anhydrous pentane. The resulting precipitate isfiltered and dried under high vacuum to provide eribulin mesylate

Oxidizing Agents Capable of Converting an Alcohol to a Carbonyl Group

Oxidizing agents capable of converting an alcohol to a carbonyl groupare known in the art. Non-limiting examples of these oxidizing agentsinclude Dess-Martin periodinane, TEMPO (in the presence of bleach orBAIB), a dimethylsulfonium compound (e.g., dimethylchlorosulfoniumchloride), aluminum trialkoxide with an excess of a ketone (e.g.,acetone), and catalytic tetrapropylammonium perruthenate (TPAP) (in thepresence of N-methylmorpholine oxide). The dimethylsulfonium compoundcan be prepared in situ under the conditions known for Parikh-Doeringoxidation, Swern oxidation, Corey-Kim oxidation, or Pfitzner-Moffattoxidation. An oxidation reaction of an alcohol to a carbonyl group(e.g., a ketone) can be performed using aluminum trialkoxide and anexcess of a ketone (e.g., acetone) under the conditions known in the artfor Oppenauer oxidation. Allylic and benzylic alcohols can also beoxidized with MnO₂.

Reducing Agents

Reducing agents that can be used in the methods of the invention arethose known in the art. A reducing agent can be an electron-transferreducing agent, a metal hydride, or a metalloid hydride. Non-limitingexamples of electron-transfer reducing agent include alkali metals inoxidation state (0), alkali earth metals in oxidation state (0), alkaliarenides, lanthanide (II) salts (e.g., SmI₂), Zn(0), Fe(0), and Mn(0).Non-limiting examples of metal hydrides and metalloid hydrides includeboron hydride compounds (e.g., NaBH₄, LiBH₄, LiB(Et)₃H, selectrides(e.g., L-selectride), and boranes (e.g., 9-BBN and alpine borane)),aluminum hydride compounds (e.g., LiAlH₄, Red-Al®, and alanes (e.g.,DIBAL)), hydrosilanes (e.g., PMHS and Ph₂SiH₂), hydrostannanes (e.g.,Bu₃SnH), copper hydride complexes (e.g., Stryker's reagent), palladiumhydride complexes, platinum hydride complexes, iridium hydridecomplexes, rhodium hydride complexes, and ruthenium hydride complexes.Reducing agents can be formed in situ, e.g., a copper hydride complexcan be formed by a reaction of a copper salt with, e.g., a boron hydridecompound or a hydrosilane. Thus, some reducing reagents (e.g., boronhydride compounds, hydrosilanes, and hydrostannanes) can be used incombination with a catalytic quantity of a metal salt (e.g., Cu, Pd, Pt,Ir, Rh, or Ru salt). Alternatively, catalytic reducing agents can bemetal salts (e.g., aluminum isopropoxide or a ruthenium complex) incombination with an alcohol, which undergo transfer hydrogenation ofcarbonyl-containing compounds without intermediacy of a metal hydride.Non-limiting examples of transfer hydrogenation reactions includeMeerwein-Ponndorf-Verley reduction (e.g., using aluminumisopropoxide/isopropanol) and Ru-catalyzed transfer hydrogenation (e.g.,Hashiguchi et al., J. Am. Chem. Soc., 117:7562-7563, 1995).

When a substrate is an α,β-unsaturated carbonyl compound (e.g., anα,β-enone), a reducing agent can be a 1,2-reducing agent or a1,4-reducing agent. For example, a reaction between an α,β-unsaturatedcarbonyl compound and a 1,2-reducing agent can afford, e.g., an allylicalcohol (or an allylic amine, if the starting compound is an enamide),whereas a reaction between an α,β-unsaturated carbonyl compound and a1,4-reducing agent can afford an α,β-saturated compound and can leavethe carbonyl group intact after work up of the reaction mixture.Non-limiting examples of 1,2-reducing agents include metal hydrides andmetalloid hydrides, e.g., aluminum hydride compounds, boron hydridecompounds (e.g., CeCl₃ with NaBH₄), and ruthenium hydride complexes.Non-limiting examples of 1,4-reducing agents include boron hydridecompounds, hydrostannanes, copper hydride complexes (e.g., Stryker'sreagent), palladium hydride complexes, platinum hydride complexes,iridium hydride complexes, rhodium hydride complexes, and rutheniumhydride complexes.

A compound having an allylic leaving group (e.g., a carboxylate, ahalide, or a sulfonate) can be treated with an allylic reducing agent toreplace the leaving group with a hydrogen atom. A non-limiting exampleof allylic reducing agent is a palladium salt in combination with aformic acid salt (e.g., trialkylammonium formate).

Masked Amines and Amine Unmasking Agents

The compounds used in the methods of the invention can contain a maskedor unmasked amine (e.g., at C.35 carbon of the structure of eribulin).An unmasked amine is —NH₂. Amine can be masked using methods known inthe art, e.g., by protecting amine with an N-protecting group.Alternatively, amine can be masked as a nitrogen-containing moiety,which can be reacted with an amine unmasking agent to afford an amine.Non-limiting examples of the nitrogen-containing moieties include azide,an imide (e.g., phathalimide), Amine unmasking agents can be those knownin the art for removing N-protecting groups from amines. In anon-limiting example, a Boc group can be removed using amine unmaskingagents known in the art, e.g., a Brønsted acid (e.g., HCl in 1,4-dioxaneor trifluoroacetic acid). When amine is masked as azide, the amine canbe unmasked by subjecting the compound containing the masked amine toStaudinger reaction conditions (e.g., by contacting with a phosphine,such as trialkylphosphine, dialkylarylphosphine, alkyldiarylphosphine,or triarylphosphine) or by reacting the compound containing the maskedamine with a reducing agent (e.g., LiAlH₄). When amine is masked as animide (e.g., phthalimide), the amine can be unmasked by reacting with anamine unmasking agent known in the art, e.g., hydrazine.

Hydroxyl Protecting Groups and Hydroxyl Protecting Group Removing Agents

Hydroxyl protecting groups can be as defined herein. In particular, ahydroxyl protecting group can be an acyl, a sulfonyl, an arylalkyl(e.g., benzyl or p-methoxybenzyl), an aryl (e.g., p-methoxyphenyl), oran optionally substituted silyl (e.g., TMS, TES, TBS, TIPS, TBDPS, orTPS). Hydroxyl protecting groups, hydroxyl protecting agents, andhydroxyl protecting reaction conditions can be selected to protectselectively certain hydroxyl groups in a compound, while leaving otherhydroxyl groups unprotected. The choice of hydroxyl protecting groupsfor a compound can facilitate subsequent deprotection strategies, assome hydroxyl protecting groups can be removed in the presence of othersusing appropriate hydroxyl protecting group removing agents. Some ofthese strategies involving the choice of silyl hydroxyl protectinggroups are discussed in, e.g., Silicon-Based Blocking Agents, Gelest,Inc., 2011.

Hydroxyl protecting group removing agents are those agents that canreact with a compound having a protected hydroxyl group to afford thecompound with a deprotected hydroxyl group. Hydroxyl protecting groupremoving agents and deprotection reaction conditions can be those knownin the art. In a non-limiting example, hydroxyl masked as silyl ethercan be unmasked by a reaction with a fluoride source (e.g., a fluoridesalt, such as KF or TBAF). Alternatively, hydroxyl protected as TMS orTES ether can be deprotected by a reaction with a Brønsted acid (e.g., acarboxylic acid). In another non-limiting example, hydroxyl protected asan ester can be deprotected by a reaction with a C₁₋₆ alkoxide (e.g.,alkali C₁₋₆ alkoxide or alkali earth C₁₋₆ alkoxide). In yet anothernon-limiting example, hydroxyl protected as an arylalkyl ether (e.g.,1-arylalk-1-yl ether) can be deprotected using a reduction reaction,e.g., with Pd/C and H₂ or with Na/NH₃. Alternatively, hydroxyl protectedas an alkoxy-arylalkyl ether (e.g., MPM ether) can be deprotected by areaction with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). In stillanother non-limiting example, hydroxyl protected as alkoxyalkyl ether(e.g., 1-alkoxyalk-1-yl) or THP ether can be deprotected by a reactionwith a Brønsted acid. Cyclic protected diols, such as acetals or ketals(e.g., as 2-alkyl-1,3-dioxolane, 2,2-dialkyl-1,3-dioxolane,2-alkyl-1,3-dioxane, or 2,2-dialkyl-1,3-dioxane), can be deprotected bya reaction with a Brønsted acid (e.g., a carboxylic acid).

Dihydroxylation and Oxidative Carbon-Carbon Bond Cleavage

Dihydroxylation reaction produces diols from olefins. The reactionconditions can be those known in the art. Dihydroxylation reaction maybe direct (e.g., Sharpless dihydroxylation, Upjohn dihydroxylation, orMilas dihydroxylation) or indirect (e.g., throughepoxidation/hydrolysis, diborylation/oxidation, orcarboxylation/hydrolysis (e.g., Woodward reaction or Prévost reaction)).A direct dihydroxylation reaction can be performed using an osmiumcomplex (e.g., OsO₄ or osmate salt). A catalytic quantity of the osmiumcomplex can be used in the dihydroxylation reactions in combination withan additional oxidizing agent (e.g., N-methylmorpholine N-oxide orhydrogen peroxide). The dihydroxylation reaction can be renderedstereoselective by including a chiral ligand (e.g., in AD-mix, which isa mixture of osmate and a chiral ligand).

When a dihydroxylation reaction is performed with an osmium complex anda periodate salt as oxidizing agent, the carbon-carbon double bond of anolefin can be cleaved to afford two carbonyl groups. The transformationof an olefin to two carbonyl groups is referred to herein as a cleavagereaction. Cleavage reaction conditions can be those known in the art.Non-limiting examples of cleavage reaction conditions can be ozonolysisreaction conditions or a reaction with an osmium complex (e.g., OsO₄ orosmate salt) and a periodate salt. A vicinal diol can be cleaved bysodium periodate or potassium permanganate.

Epimerizations

Epimerization reactions can be used to invert a stereogenic centerhaving an undesired stereochemical identity. For example, throughepimerization, R stereogenic center can be converted to S stereogeniccenter and vice versa. Epimerization of a stereogenic sp³-carbon bondedto one hydrogen atom and to one hydroxyl group can be achieved through areaction sequence involving oxidation of the hydroxyl group to acarbonyl group followed by a 1,2-reduction reaction. The 1,2-reductionreaction can provide the desired stereochemical identitydiastereoselectively, or the reaction can be carried out using a chiralcatalyst, chiral auxiliary, or a chiral reducing agent. Non-limitingexamples of chiral reducing agents include alpine borane and prapineborane. Non-limiting examples of 1,2-reduction reactions involvingchiral catalysts are Corey-Bakshi-Shibata reduction, Noyorihydrogenation, and Noyori transfer hydrogenation, Theoxidation/reduction reaction sequence can be carried out in situ usingdynamic kinetic resolution. A dynamic kinetic resolution can furtherinvolve a reaction with a hydroxyl protecting agent, which removes thedesired stereoisomer from the reduction/oxidation equilibrium. In anon-limiting example, a dynamic kinetic resolution of chiral secondaryalcohols can involve reduction/oxidation equilibration usingη⁵-Ph₅CpRu(CO)₂H in combination with enantioselective esterificationusing isopropenyl acetate catalyzed by a lipase enzyme (e.g., lipase Bfrom Candida Antarctica, see, e.g., Martin-Matute et al., J. Am. Chem.Soc., 127:8817-8825, 2005).

Epimerization can also be carried out on a compound containing atetrahydropyran-2-yl-acetaldehyde moiety, in which carbon 2 of the pyranring exhibits an undesired stereochemical identity. Contacting thiscompound with L-proline can provide equilibrium between twostereoisomers. If other, non-equilibrating stereogenic centers arepresent in the compound, the most stable stereoisomer will be present ina larger quantity relative to other stereoisomer(s) in equilibrium withthe most stable stereoisomer.

The following examples are meant to illustrate the invention. They arenot meant to limit the invention in any way.

EXAMPLES Example 1 Preparation of the C.1-C.15 Fragment

(2S,3S,4R,5R)-2-allyl-4-(benzyloxy)-5-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)tetrahydrofuran-3-ol

A 3:1 diasteremeric mixture (600 g) of(R)-3-((2R,3R,4S,5S)-5-allyl-3-(benzyloxy)-4-hydroxytetrahydrofuran-2-yl)propane-1,2-diyldibenzoateand(S)-3-((2R,3R,4S,5S)-5-allyl-3-(benzyloxy)-4-hydroxytetrahydrofuran-2-yl)propane-1,2-diyldibenzoatewas dissolved in methanol (1800 mL) at ambient temperature. Potassiumcarbonate (241 g, 1742 mmol) was added, and the resulting mixture wasstirred between 55 and 60° C. for 4 h. Water (1500 mL) was added, andthe resulting mixture was extracted four times with n-heptane (2400 mLeach time). The aqueous layer was diluted with water (1200 mL) andextracted twice with ethyl acetate (3000 mL each time). The combinedorganic layers were concentrated in vacuo and azeotroped twice withtoluene (1200 mL, each time). Upon addition of the acetone (1200 mL),white insoluble materials were generated. The mixture was filteredthrough 200 g of silica gel pad, which was then rinsed with acetone(1200 mL). The combined filtrate was concentrated in vacuo to give 216 gof brown oil, which was dissolved in acetone (864 mL) at ambienttemperature. 2,2-Dimethoxypropane (103 mL, 841 mmol) and sulfuric acid(1.9 mL, 35 mmol) were added. The resulting mixture was stirred for 4 hand then treated with saturated aqueous NaHCO₃ (8%) (216 mL) and water(540 mL). The resulting mixture was extracted twice with MTBE (864 mLeach time). The combined organic layers were washed twice with 30%aqueous NaCl (430 mL each time) and then three times with water (450 mLeach time). The resulting organic layer was concentrated in vacuo andazeotroped twice with toluene (864 mL) to give 219 g of the targetproduct as a brown oil. ¹H NMR (3:1 diastereomeric mixture, 400 MHz,CDCl₃) δ ppm 1.31 (s, 3 H (minor)) 1.36 (s, 3 H (major)) 1.40 (s, 3 H)1.93 (t, J=6.4 Hz, 2 H) 1.96-2.09 (m, 1 H) 2.32-2.41 (m, 1 H) 2.42-2.52(m, 1 H) 3.53-3.62 (m, 1 H) 3.66 (td, J=6.7, 4.7 Hz, 1 H) 3.79 (dd,J=4.7, 2.1 Hz, 1 H (major)) 3.81 (dd, J=4.7, 2.1 Hz, 1 H (minor))3.97-4.04 (m, 1 H) 4.06-4.12 (m, 1 H) 4.12-4.17 (m, 1 H) 4.24 (dt,J=13.1, 6.5 Hz, 1 H) 4.51 (d, J=12.0 Hz, 1 H (minor)) 4.54 (d, J=12.0Hz, 1 H (major)) 4.65 (d, J=11.7 Hz, 1 H (major)) 4.66 (d, J=12.0 Hz, 1H (minor)) 5.05-5.18 (m, 2 H) 5.77-5.93 (m, 1 H) 7.28-7.41 (m, 5 H).

4-(((2R,3S,4S,5S)-5-allyl-3-(benzyloxy)-4-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)methyl)-2,2-dimethyl-1,3-dioxolane

A 3:1 diastereomeric mixture of(2S,3S,4R,5R)-2-allyl-4-(benzyloxy)-5-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)tetrahydrofuran-3-oland(2S,3S,4R,5R)-2-allyl-4-(benzyloxy)-5-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)tetrahydrofuran-3-ol(219 g, 629 mmol) was azeotroped with anhydrous THF (329 mL). Theresulting oil was added into a reactor with DMF (329 mL). TBAI (46.4 g,126 mmol) was added, and the resulting mixture was cooled to atemperature ranging from 0 to 5° C. 1.0 M tert-Butyl alcohol, potassiumderivative (691 mL, 691 mmol) was added at such rate to maintain theinternal temperature below 10° C. Upon addition, the reaction wasallowed to stir for 15 minutes. alpha-Chloro-4-methoxytoluene (98 mL,720 mmol) was then added at such rate to maintain internal temperaturebelow 15° C. Upon addition, the reaction was stirred between 0-5° C.After complete consumption of the starting material, the reaction wasquenched with MeONa (25%) in MeOH solution (21.6 mL, 94.3 mmol) dilutedin anhydrous methanol (288 mL) at such a rate that internal temperatureremained below 10° C. The mixture was then allowed to warm to 20-25° C.and then concentrated in vacuo to remove volatiles. The remainingsolution was partitioned between water (1095 mL) and MTBE (1643 mL). Theorganic layer was washed twice with 30% aqueous NaCl (876 mL), driedover MgSO₄, filtered and concentrated in vacuo. The resulting residuewas diluted with MTBE (219 mL), and remaining solid was filtered off.The filtrate was concentrated in vacuo to give 295 g of the targetproduct as a reddish brown oil. ¹H NMR (3:1 diastereomeric mixture, 400MHz, CDCl₃) δ ppm 1.31 (s, 3 H (minor)) 1.35 (s, 3 H (major)) 1.37-1.42(m, 3 H) 1.87-2.03 (m, 2 H) 2.26-2.52 (m, 2 H) 3.57 (t, J=7.9 Hz, 1 H)3.72 (dd, J=7.3, 3.5 Hz, 1 H (major)) 3.74 (d, J=3.2 Hz, 1 H (minor))3.78-3.86 (m, 5 H) 3.98-4.14 (m, 2 H) 4.15-4.30 (m, 1 H) 4.33-4.41 (m, 2H) 4.42-4.46 (m, 1 H) 4.57 (d, J=12.0 Hz, 1 H) 5.00-5.10 (m, 2 H)5.73-5.91 (m, 1 H) 6.85-6.91 (m, 2 H) 7.19-7.24 (m, 2 H) 7.27-7.39 (m, 5H)

2-((2S,3S,4S,5R)-4-(benzyloxy)-5-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)acetaldehyde

3:1 diastereomeric mixture of2-((2S,3S,4S,5R)-4-(benzyloxy)-5-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)acetaldehydeand2-((2S,3S,4S,5R)-4-(benzyloxy)-5-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)acetaldehyde(100 g, 213 mmol) was dissolved in 1,4-dioxane (600 mL) and water (200mL). 2,6-Lutidine (49.7 mL, 427 mmol) and a solution of osmic acid (2.5wt %, 25 mL, 2.458 mmol) in t-BuOH were added. The resulting mixture wascooled to a temperature below 20° C. and sodium metaperiodate (137 g,640 mmol) was added. After being stirred for 5 h at ambient temperature,the reaction mixture was treated with water (1250 mL). The resultingmixture was extracted twice with toluene (1000 mL each time). Thecombined organic layers were washed sequentially with a solution ofsodium sulfite (40.3 g, 320 mmol) in water (200 mL), 1.0 M hydrochloricacid in water (500 mL, 500 mmol), saturated aqueous NaHCO₃ (8%) (200mL), and 30% aqueous NaCl (200 mL). The organic layer was concentratedin vacuo, and the residue was filtered through a silica-gel pad (150mL), which was rinsed with n-heptane/ethyl acetate (1/1=1000 mL).Concentration in vacuo provided 102 g of the target product as darkbrown oil. ¹H NMR (3:1 diastereomeric mixture, 400 MHz, CDCl₃) δ ppm1.31 (s, 1 H(minor)) 1.35 (s, 3 H(major)) 1.39 (s, 3 H) 1.87-2.14 (m, 2H) 2.66 (dd, J=5.8, 1.8 Hz, 1 H) 2.70-2.78 (m, 1 H) 3.55 (dd, J=8.2, 7.3Hz, 1 H) 3.76 (dd, J=2.9, 0.8 Hz, 1 H(major)) 3.77 (dd, J=2.7, 0.6 Hz, 1H(minor)) 3.79-3.84 (m, 4 H) 4.00 (dd, J=7.8, 6.0 Hz, 1 H(major)) 4.06(dd, J=8.2, 5.8 Hz, 1 H(minor)) 4.12 (dt, J=8.9, 3.8 Hz, 1 H) 4.17-4.24(m, 1 H) 4.28 (ddd, J=7.3, 5.6, 2.9 Hz, 1 H) 4.36-4.50 (m, 3 H) 4.54 (d,J=12.2 Hz, 1 H) 4.55 (d, J=11.9 Hz, 1 H) 6.85-6.91 (m, 2 H) 7.15-7.39(m, 7 H) 9.73 (t, J=2.0 Hz, 1 H)

2-((2S,3S,4S,5R)-4-(benzyloxy)-5-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)-1-(furan-2-yl)ethan-1-ol

Furan (22.40 mL, 308.0 mmol) and THF (800 mL) were added into a reactorand cooled down to 0° C. n-BuLi (1.6 M, 110 mL, 276 mmol) was addedwhile keeping the internal temperature below 15° C. After being stirredfor 1 h at a temperature between 10 and 20° C., the resulting solutionwas cooled to a temperature below −20° C. A solution of a 3:1diastereomeric mixture of2-((2S,3S,4S,5R)-4-(benzyloxy)-5-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)acetaldehydeand2-((2S,3S,4S,5R)-4-(benzyloxy)-5-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)acetaldehyde(102 g, 212 mmol) in THF (300 mL) was added while keeping the internaltemperature below −10° C. The resulting reaction mixture was stirred ata temperature between −5 and −15° C. for 1 h. Saturated aqueous NH₄Cl(27 wt %) (500 mL) and water (200 mL) were added, and the mixture wasallowed to warm to ambient temperature. The layers were separated, andthe organic layer was washed twice with 30% aqueous NaCl (400 mL) andconcentrated in vacuo. The residue was filtered through a silica gel pad(300 mL), rinsing with n-heptane/ethyl acetate (3/2, 1300 mL).Concentration of the filtrate afforded 94 g of the target product as abrown oil.

4-(((2R,3S,4S,5S)-3-(benzyloxy)-54-(E)-2-(furan-2-yl)vinyl)-4-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)methyl)-2,2-dimethyl-1,3-dioxolane

2-((2S,3S,4S,5R)-4-(benzyloxy)-5-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)-1-(furan-2-yl)ethan-1-ol(94 g) was dissolved in dimethylacetamide (893 mL).Methyltriphenoxyphosphonium iodide (99 g, 218 mmol) was added whilekeeping the internal temperature below 25° C. The resulting reaction waskept stirring between 20-25° C. in dark for 2.5 h. The reaction mixturewas diluted with MTBE (1410 mL) and cooled down below 10° C. A solutionof KOH (88 g, 1571 mmol) in water (1128 mL) was added while keeping theinternal temperature below 30° C. The aqueous layer was separated outand extracted twice with MTBE (940 mL). The combined organic layers werewashed three times with 30% aqueous NaCl (1128 mL) and concentrated invacuo. The residue was filtered through a silica gel pad (200 mL), whichwas then rinsed with n-heptane/ethyl acetate (2/1, 1500 mL).Concentration of the filtrate gave 87.9 g of the target product as brownoil. ¹H NMR (3:1 diastereomeric mixture, 400 MHz, CDCl₃) δ ppm 1.31 (s,3 H(minor)) 1.35 (s, 3 H(major)) 1.40 (s, 3 H) 1.87-2.20 (m, 2 H) 3.58(t, J=7.3 Hz, 1 H) 3.78-3.81 (m, 3 H) 3.88 (d, J=3.4 Hz, 1 H(major))3.89 (d, J=3.7 Hz, 1 H(minor)) 4.03 (dd, J=7.8, 6.0 Hz, 1 H(minor)) 4.09(dd, J=8.2, 6.1 Hz, 1 H(major)) 4.17 (dt, J=9.5, 3.7 Hz, 1 H) 4.22-4.31(m, 1 H) 4.36 (dd, J=7.3, 3.4 Hz, 1 H) 4.42-4.51 (m, 3 H) 4.59 (d,J=12.5 Hz, 1 H(major)) 4.60 (d, J=11.9 Hz, 1 H(minor)) 6.15-6.26 (m, 2H) 6.37 (dd, J=3.2, 2.0 Hz, 1 H) 6.39-6.49 (m, 1 H) 6.84-6.89 (m, 2 H)7.19-7.24 (m, 2 H) 7.26-7.38 (m, 5 H)

(2R)-1-((2S,3R,4S,5R)-4-(benzyloxy)-5-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)-2-(furan-2-yl)ethane-1,2-diol

To a reactor were added (DHQ)₂PHAL (1.267 g, 1.627 mmol), potassiumosmium(VI) oxide (0.216 g, 0.651 mmol), potassium carbonate (67.5 g, 488mmol), and potassium ferricyanide(III) hydrate (161 g, 488 mmol). Water(847 mL) and 2-methylpropan-2-ol (424 mL) were added. The resultingmixture was cooled below 7° C. Methane sulfonamide (18.57 g, 195 mmol)followed by a solution of a 3:1 diastereomeric mixture of(R)-4-(((2R,3S,4S,5S)-3-(benzyloxy)-5-((E)-2-(furan-2-yl)vinyl)-4-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)methyl)-2,2-dimethyl-1,3-dioxolaneand(S)-4-(((2R,3S,4S,5S)-3-(benzyloxy)-5-((E)-2-(furan-2-yl)vinyl)-4-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)methyl)-2,2-dimethyl-1,3-dioxolane(84.7 g, 162.693 mmol) in tert-butanol (424 mL) was added. The resultingmixture was stirred for 3 days between 13-18° C. Sodium sulfite (103 g,813 mmol) and water (339 mL) were added, and the resulting mixture wasstirred for 30-60 min while warming to ambient temperature. The mixturewas extracted twice with ethyl acetate (2100 mL). The combined organiclayers were washed with 2M aqueous KOH (296 mL) and 30% aqueous NaCl(424 mL). Concentration in vacuo followed by silica gel plugpurification using a 25-66% gradient of ethyl acetate in n-heptane aseluent provided 71.6 g of the target product as a brown oil. ¹H NMR (3:1diastereomeric mixture, 400 MHz, CDCl₃) δ ppm 1.33-1.38 (m, 3 H)1.39-1.42 (m, 3 H) 1.85-2.09 (m, 2 H) 3.57 (t, J=7.8 Hz, 1 H) 3.78 (d,J=3.1 Hz, 1 H) 3.81 (s, 3 H) 3.83-3.87 (m, 1 H) 3.89 (br. s., 1 H)4.04-4.12 (m, 3 H) 4.16-4.24 (m, 1 H) 4.34-4.49 (m, 3 H) 4.62 (d, J=11.6Hz, 1 H(major)) 4.63 (d, J=11.6 Hz, 1 H(minor)) 4.73 (d, J=7.0 Hz, 1H(major)) 4.76 (d, J=6.1 Hz, 1 H(minor)) 6.34-6.37 (m, 2 H) 6.86-6.91(m, 2 H) 7.16-7.24 (m, 2 H) 7.27-7.44 (m, 6 H).

3-((2R,3S,4R,5S)-3-(benzyloxy)-5-((2R)-2-(furan-2-yl)-1,2-dihydroxyethyl)-4-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)propane-1,2-diol

3:1 diastereomeric mixture of(2R)-1-((2S,3R,4S,5R)-4-(benzyloxy)-5-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)-2-(furan-2-yl)ethane-1,2-dioland(2R)-1-((2S,3R,4S,5R)-4-(benzyloxy)-5-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)-2-(furan-2-yl)ethane-1,2-diol(71.6 g, 129 mmol) was dissolved in acetic acid (501 mL). Water (125 mL)was added, and the resulting mixture was stirred at ambient temperatureovernight. The reaction mixture was concentrated in vacuo and azeotropedwith toluene (500 mL). The residue was filtered through silica-gel pad(200 mL), which was then rinsed with n-heptane/ethyl acetate (1/1, 1 L)and ethyl acetate (3.5 L). Concentration of the filtrate gave 69.4 g ofthe target product as brown oil.

3-((2R,3S,4R,5R)-5-((1S)-acetoxy((2R)-6-acetoxy-3-oxo-3,6-dihydro-2H-pyran-2-yl)methyl)-3-(benzyloxy)-4-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)propane-1,2-diyldiacetate

A 3:1 diastereomeric mixture of(R)-3-((2R,3S,4R,5S)-3-(benzyloxy)-5-((1R,2R)-2-(furan-2-yl)-1,2-dihydroxyethyl)-4-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)propane-1,2-dioland(S)-3-((2R,3S,4R,5S)-3-(benzyloxy)-5-((1R,2R)-2-(furan-2-yl)-1,2-dihydroxyethyl)-4-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)propane-1,2-diol(69.4 g) was dissolved in THF (989 mL) and water (247 mL) and cooleddown below 5° C. Sodium bicarbonate (21.53 g, 256.3 mmol) and sodiumacetate (10.51 g, 128.1 mmol) were added. NBS (23.94 g, 134.5 mmol) wasadded while keeping the internal temperature below 5° C. After beingstirred for 1 h at a temperature between 0 and 5° C., the reactionmixture was treated with a solution of potassium iodide (10.63 g, 64.06mmol) in water (165 mL) and diluted with EtOAc (2000 mL). The organiclayer was washed with a solution of sodium thiosulfate (16.21 g, 102.5mmol) in water (198 mL) followed by 30% aqueous NaCl (132 mL). Solventswere removed in vacuo. The resulting residue (71 g) was dissolved indichloromethane (613 mL) and cooled down to 0° C. Pyridine (198 mL, 2444mol), acetic anhydride (121 mL, 1285 mol) and 4-dimethylaminopyridine(1.57 g, 12.8 mmol) were added. After being stirred overnight at atemperature between 0 and 15° C., the reaction mixture was treated withsaturated aqueous NH₄Cl (27 wt %) (545 mL) and water (136 mL). Thelayers were separated, and the aqueous layer was extracted withdichloromethane (341 mL). The combined organic layers were washed twicewith 0.5 M aqueous hydrochloric acid (409 mL) followed by 30% aqueousNaCl (477 mL). Concentration followed by filtration through a silica gelpad (60 mL), which was then rinsed with heptane/ethyl acetate (1/1, 1500mL), provided 92 g of the target product as a brown oil.

3-((2R,3S,4R,5R)-5-((1S)-acetoxy((2R)-6-allyl-3-oxo-3,6-dihydro-2H-pyran-2-yl)methyl)-3-(benzyloxy)-4-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)propane-1,2-diyldiacetate

3-((2R,3S,4R,5R)-5-((1S)-Acetoxy((2R)-6-acetoxy-3-oxo-3,6-dihydro-2H-pyran-2-yl)methyl)-3-(benzyloxy)-4-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)propane-1,2-diyldiacetate(92 g, 129 mmol) was dissolved in acetonitrile (902 mL) and cooled to−15° C. Allyltrimethylsilane (51.3 mL, 323 mmol) followed by BF₃.OEt₂(21.26 mL, 167.7 mmol) was added while keeping internal temperaturebelow −10° C. The resulting solution was stirred at a temperaturebetween −10 and 0° C. until the reaction was complete. Saturated aqueousNaHCO₃ (8%) (902 mL) and MTBE (721 mL) were then added, and theresulting mixture was allowed to warm to ambient temperature. The layerswere separated, and the aqueous layer was extracted with MTBE (721 mL).The combined organic layers were washed twice with 30% aqueous NaCl (721mL) and concentrated in vacuo. The residue was diluted with MTBE (1500mL) and washed sequentially with 1M HCl (250 mL), saturated aqueousNaHCO₃ (8%) (250 mL), and 30% aqueous NaCl (250 mL). Concentrationfollowed by filtration through a silica gel pad (100 mL), which was thenrinsed with n-heptane/ethyl acetate (2/3, 1200 mL), provided 54.2 g ofthe target product as a brown oil.

3-((2R,3R,4R,5R)-5-((1S)-acetoxy((2R)-6-allyl-3-oxo-3,6-dihydro-2H-pyran-2-yl)methyl)-3-(benzyloxy)-4-hydroxytetrahydrofuran-2-yl)propane-1,2-diyldiacetate

3-((2R,3S,4R,5R)-5-((1S)-acetoxy((2R)-6-allyl-3-oxo-3,6-dihydro-2H-pyran-2-yl)methyl)-3-(benzyloxy)-4-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)propane-1,2-diyldiacetate(54.2 g) was dissolved in dichloromethane (542 mL) and treated withwater (136 mL) and DDQ (25.3 g, 111 mmol). After being stirred for 2 hat ambient temperature, the reaction mixture was diluted withdichloromethane (700 mL) and water (700 mL). Saturated aqueous NaHCO₃(8%) (870 mL) and sodium thiosulfate (35.2 g, 223 mmol) were added, andthe resulting mixture was stirred at ambient temperature for 10 min. Thelayers were separated, and the aqueous layer was extracted withdichloromethane (271 mL). The combined organic layers were washed withsaturated aqueous NaHCO₃ (8%) (325 mL) and 30% aqueous NaCl (217 mL).Concentration in vacuo and purification by silica gel columnchromatography using a 20-60% gradient of ethyl acetate in n-heptane aseluent afforded 31.2 g of the target product as a brown oil. 1H NMR (a9:3:3:1 mixture of 4 diastereomers, 400 MHz, CDCl₃) δ ppm 1.84-1.98 (m,2 H) 2.04 (d, J=12.9 Hz, 9 H) 2.43 (d, J=8.2 Hz, 2 H) 3.89 (dt, J=7.6,2.1 Hz, 1 H) 3.98-4.06 (m, 2 H) 4.07-4.18 (m, 2 H) 4.34 (dd, J=11.9, 3.3Hz, 1 H) 4.43 (d, J=5.1 Hz, 1 H) 4.55 (d, J=11.7 Hz, 1 H) 4.60-4.65 (m,1 H) 4.66-4.73 (m, 1 H) 5.12-5.23 (m, 3 H) 5.51 (dd, J=6.6, 5.1 Hz, 1 H(major)) 5.55 (dd, J=5.9, 4.7 Hz, 1 H(minor)) 5.75-5.88 (m, 1 H) 6.12(dd, J=10.6, 2.3 Hz, 1 H) 6.90 (dd, J=10.4, 1.4 Hz, 1 H(minor)) 6.95(dd, J=10.6, 2.3 Hz, 1 H(major)) 7.27-7.40 (m, 5 H)

3-((2R,3S,5S)-5-((1R)-acetoxy((2R)-6-allyl-3-oxo-3,6-dihydro-2H-pyran-2-yl)methyl)-3-(benzyloxy)-4-oxotetrahydrofuran-2-yl)propane-1,2-diyldiacetate

To3-((2R,3R,4R,5R)-5-((1S)-acetoxy((2R)-6-allyl-3-oxo-3,6-dihydro-2H-pyran-2-yl)methyl)-3-(benzyloxy)-4-hydroxytetrahydrofuran-2-yl)propane-1,2-diyldiacetate(27.4 g, 48.9 mmol) was added dichloromethane (219 mL) at ambienttemperature. Sodium bicarbonate (12.32 g, 146.6 mmol), Dess-Martinperiodinane (30.1 g, 70.872 mmol) and water (0.176 mL, 9.78 mmol) wereadded. The resulting mixture was stirred at ambient temperature untilall starting material was consumed. It was then diluted with water (301mL) and MTBE (301 mL). Sodium bicarbonate (12.32 g, 146.6 mmol) andsodium thiosulfate (19.32 g, 122.2 mmol) were added, and the resultingmixture was stirred at ambient temperature over 10 min. The layers wereseparated, and the aqueous layer was extracted with MTBE (219 mL). Thecombined organic layers were washed with saturated aqueous NaHCO₃ (8%)(137 mL) and 30% aqueous NaCl (137 mL). Concentration in vacuo followedby azeotroping with toluene provided 33.1 g of the target product as adark brown oil.

3-((2R,3S,5S)-5-((1R)-acetoxy((2R)-6-allyl-3-oxo-3,6-dihydro-2H-pyran-2-yl)methyl)-3-(benzyloxy)-4-hydroxytetrahydrofuran-2-yl)propane-1,2-diyldiacetate

3-((2R,3S,5S)-5-((1R)-acetoxy((2R)-6-allyl-3-oxo-3,6-dihydro-2H-pyran-2-yl)methyl)-3-(benzyloxy)-4-oxotetrahydrofuran-2-yl)propane-1,2-diyldiacetate was dissolved in dichloromethane (406 mL) and MeOH (406 mL)and cooled to a temperature below −75° C. Sodium borohydride (2.75 g,72.3 mmol) was added portionwise while keeping the internal temperaturebelow −75° C. After 1 h, acetone (95 mL, 1290 mmol) was added whilekeeping the internal temperature below −75° C. Saturated aqueous NH₄Cl(27 wt %) (216 mL), water (108 mL) and MTBE (325 mL) were added. Theresulting mixture was allowed to warm up to ambient temperature. Thelayers were separated and the aqueous layer was extracted with MTBE (271mL). The combined organic layers were washed twice with 30% aqueous NaCl(189 mL) and dried over MgSO₄. Filtration followed by concentration invacuo provided 30.8 g of brown thick oil, which was dissolved indichloromethane (271 mL). To the resulting solution was added manganesedioxide (42.1 g, 484 mmol). The resulting slurry was vigorously stirredat ambient temperature overnight. 40 g of Celite® was then added, andthe resulting slurry was stirred at ambient temperature for 20 min.Filtration through a Celite® pad, concentration in vacuo, andpurification by silica gel column chromatography using n-heptane/ethylacetate (1/2) as eluent gave 23.8 g of the target product as a foamsolid.

3-((2R,3S,5S)-5-((1R)-acetoxy((2R)-6-allyl-3-oxotetrahydro-2H-pyran-2-yl)methyl)-3-(benzyloxy)-4-hydroxytetrahydrofuran-2-yl)propane-1,2-diyldiacetate

3-((2R,3S,5S)-5-((1R)-acetoxy((2R)-6-allyl-3-oxo-3,6-dihydro-2H-pyran-2-yl)methyl)-3-(benzyloxy)-4-hydroxytetrahydrofuran-2-yl)propane-1,2-diyldiacetate(20 g, 35.7 mmol) was dissolved in deoxygenated toluene (460 mL) atambient temperature. The resulting solution was purged with nitrogen for1 h and deoxygenated (purged with nitrogen for 40 min) water (1.22 mL,67.8 mmol) was added. Hydrido(triphenylphosphine)copper(I) hexamer (16.0g, 8.16 mmol) was added in 3 portions. The resulting red slurry wasstirred over 4 h. Upon completion, the reaction was exposed to air.Copper-containing decomposition products precipitated out. The resultingbrown slurry was filtered through a Celite pad, which was then rinsedwith toluene until no product was observed in eluent. Concentration invacuo followed by purification by column chromatography using a 20-66%gradient of ethyl acetate in n-heptane as eluent gave 18.07 g of thetarget product as a brown oil.

3-((2R,3S,3aS,8aR,9S,9aR)-9-acetoxy-7-allyl-3-(benzyloxy)-4a-methoxydecahydrofuro[3,2-b]pyrano[2,3-e]pyran-2-yl)propane-1,2-diyldiacetate

3-((2R,3S,5S)-5-((1R)-acetoxy((2R)-6-allyl-3-oxotetrahydro-2H-pyran-2-yl)methyl)-3-(benzyloxy)-4-oxotetrahydrofuran-2-yl)propane-1,2-diyldiacetate(23.4 g, 41.6 mmol) was dissolved in methanol (281 mL).((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonicacid (1.1 g, 5.0 mmol) was added, and the resulting solution was stirredat 60° C. until all starting material was consumed. The mixture wascooled to ambient temperature and treated with TEA (0.870 mL, 6.24mmol). Solvents were removed, and the residue was dissolved in ethylacetate (468 mL). The resulting solution was washed with 30% aqueousNaCl (70.2 mL), dried over MgSO₄, filtered, and concentrated in vacuo.The residue was dissolved in dichloromethane (140 mL) and pyridine (46.8mL) at ambient temperature. Acetic anhydride (23.59 mL, 249.6 mmol) and4-dimethylaminopyridine (0.508 g, 4.16 mmol) were added, and theresulting solution was stirred at ambient temperature for 1 h. Thereaction mixture was treated with saturated aqueous NH₄Cl (27 wt %) (140mL), water (46.8 mL) and MTBE (281 mL). The organic layer was separatedand washed sequentially with 1M aqueous hydrochloric acid (94 mL),saturated aqueous NaHCO₃ (8%) (70.2 mL), and 30% aqueous NaCl (70.2 mL).Drying over MgSO₄, filtration, concentration and purification by silicagel column chromatography using a 25-40% gradient of ethyl acetate inn-heptane as eluent provided 12.3 g of the target product as a palebrown oil.

¹H NMR (9:3:3:1 mixture of 4 diastereomers, CDCl₃) δ ppm 1.29-1.48 (m, 1H) 1.54-1.78 (m, 3 H) 1.93-2.16 (m, 11 H) 2.17-2.40 (m, 2 H) 3.25 (s, 3H(minor 1)) 3.29 (s, 3H(minor 2)) 3.30 (s, 3H (major)) 3.55 (d, J=11.1Hz, 1 H (major)) 3.56 (d, J=11.4 Hz, 1 H (minor)) 3.62-3.75 (m, 1 H)3.98-4.26 (m, 4 H) 4.29-4.38 (m, 1 H) 4.39-4.45 (m, 1 H) 4.50 (d, J=11.7Hz, 1 H (minor 2)) 4.52 (d, J=12.0 Hz, 1 H (major)) 4.57 (d, J=12.0 Hz,1 H (minor 3)) 4.59 (d, J=12.3 Hz, 1 H (minor 1)) 4.73-4.83 (m, 1 H)4.96-5.09 (m, 2 H) 5.18-5.27 (m, 1 H) 5.26 (dd, J=11.3, 6.0 Hz, 1 H)5.37 (dd, J=11.4, 5.9 Hz, 1 H (major)) 5.72 (dd, J=17.1, 10.1 Hz, 1 H(minor)) 7.27-7.40 (m, 5 H)

3-((2R,3S,3aS,7R,8aR,9S,9aR)-9-acetoxy-3-(benzyloxy)-7-(2-hydroxyethyl)-4a-methoxydecahydrofuro[3,2-b]pyrano[2,3-e]pyran-2-yl)propane-1,2-diyldiacetate

3-((2R,3S,3aS,8aR,9S,9aR)-9-acetoxy-7-allyl-3-(benzyloxy)-4a-methoxydecahydrofuro[3,2-b]pyrano[2,3-e]pyran-2-yl)propane-1,2-diyldiacetate(13.5 g, 23.4 mmol) was dissolved in 1,4-dioxane (176 mL) and water(58.1 mL). 2,6-Lutidine (8.18 mL, 70.2 mmol), 4.0% osmic acid in water(3.27 mL, 0.515 mmol), and sodium metaperiodate (25.04 g, 117.1 mmol)were added. The resulting solution was stirred at ambient temperatureuntil all starting material was consumed. Upon completion, water (203mL) and toluene (203 mL) were added. The aqueous layer was separated andextracted with toluene (135 mL). The combined organic layers were washedsequentially with 1M hydrochloric acid (67.5 mL, 67.5 mmol), saturatedaqueous NaHCO₃ (8%) (54.0 mL), 10% aqueous Na₂S₂O₃ (40.5 mL), and 30%aqueous NaCl (81 mL). The resulting solution was dried over MgSO₄ andconcentrated in vacuo. The residue (15.6 g) was dissolved in methanol(201 mL) at ambient temperature. The resulting solution was cooled to atemperature below 10° C., and L-proline (0.801 g, 6.96 mmol) was addedin one portion. The resulting solution was stirred overnight whilewarming to ambient temperature. After being stirred for additional 6 hat ambient temperature, the reaction mixture was diluted with MTBE (335mL), and saturated aqueous NaHCO₃ (8%) (201 mL) and water (108 mL) wereadded. The layers were separated, and the aqueous layer was extractedtwice with MTBE (201 mL each time). The combined organic layers werewashed twice with 30% aqueous NaCl (107 mL), dried over MgSO₄, andconcentrated in vacuo. The residue (21 g) was dissolved in methanol (201mL) and cooled to 0° C. Sodium borohydride (1.14 g, 30.1 mmol) was addedin 5 portions. Once the reaction was complete, saturated aqueous NH₄Cl(27 wt %) (134 mL) and water (67.1 mL, 3723.506 mmol) were added. Themixture was extracted twice with ethyl acetate (470 mL). The combinedorganic layer was washed with 30% aqueous NaCl (107 mL), dried overMgSO₄, filtered, and concentrated in vacuo. The residue was filteredthrough a silica gel pad (200 mL), which was then rinsed withn-heptane/ethyl acetate (1/1, 400 mL) and ethyl acetate (1200 mL). Thecombined filtrate was concentrated in vacuo to give 10.75 g of thetarget product.

3-((2R,3S,3aS,7R,8aR,9S,9aR)-9-acetoxy-3-(benzyloxy)-4a-methoxy-7-(2-(pivaloyloxy)ethyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-2-yl)propane-1,2-diyldiacetate

3-((2R,3S,3aS,7R,8aR,9S,9aR)-9-acetoxy-3-(benzyloxy)-7-(2-hydroxyethyl)-4a-methoxydecahydrofuro[3,2-b]pyrano[2,3-e]pyran-2-yl)propane-1,2-diyldiacetate(10.6 g, 18.3 mmol) was dissolved in dichloromethane (106 mL) at 17-22°C. Pyridine (10.60 mL, 131 mmol), pivaloyl chloride (6.74 mL, 54.8mmol), and 4-dimethylaminopyridine (0.446 g, 3.65 mmol) were added.After 2 h at ambient temperature, saturated aqueous NaHCO₃ (8%) (106mL), water (31.8 mL), and MTBE (159 mL) were added. After 10 min ofbeing stirred at ambient temperature, the layers were separated, and theorganic layer was washed with saturated aqueous NaHCO₃ (8%) (53.0 mL)and 30% aqueous NaCl (53.0 mL). Drying over MgSO₄, concentration invacuo, and purification by silica-gel column chromatography using a33-50% gradient of ethyl acetate in n-heptane as eluent provided 12.1 gof the target product as a pale brown oil.

¹H NMR (major isomer only, 400 MHz, CDCl₃) δ ppm 1.14-1.20 (m, 9 H)1.43-1.88 (m, 6 H) 1.93-2.14 (m, 1 H) 2.02 (s, 3 H) 2.03 (s, 3 H) 2.05(s, 3 H) 2.16-2.28 (m, 1 H) 3.26 (s, 3 H) 3.32-3.42 (m, 1 H) 3.76 (s, 1H) 4.01-4.20 (m, 6 H) 4.24 (t, J=4.0 Hz, 1 H) 4.36 (dd, J=12.0, 2.9 Hz,1 H) 4.58 (d, J=12.3 Hz, 1 H) 4.80 (dd, J=12.0, 3.8 Hz, 1 H) 5.02 (s, 1H) 5.13-5.29 (m, 2 H) 7.30-7.39 (m, 5 H)

3-((2R,3S,3aS,7R,8aR,9S,9aR)-9-acetoxy-3-hydroxy-4a-methoxy-7-(2-(pivaloyloxy)ethyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-2-yl)propane-1,2-diyldiacetate

3-((2R,3S,3aS,7R,8aR,9S,9aR)-9-acetoxy-3-(benzyloxy)-4a-methoxy-7-(2-(pivaloyloxy)ethyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-2-yl)propane-1,2-diyldiacetate(12.08 g, 18.17 mmol) was dissolved in methanol (121 mL) and EtOAc (60.4mL). 10% Palladium on carbon (4.8 g) wasadded, and the resulting mixturewas treated with hydrogen using a hydrogen balloon at ambienttemperature until all starting material was consumed. The resultingmixture was purged with nitrogen and filtered through a Celite® pad (20g), which was then rinsed with EtOAc until no target product remained inthe pad. The filtrate was concentrated in vacuo and azeotroped withtoluene (72.5 mL). The residue was filtered through a silica-gel pad(200 mL), which was then rinsed with n-heptane/ethyl acetate (50% to100%). Concentration of the combined filtrate provided 9.5 g of thetarget product.

3-((2R,3S,3aR,7R,8aR,9S,9aR)-9-acetoxy-3-((diisopropylsilyl)oxy)-4a-methoxy-7-(2-(pivaloyloxy)ethyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-2-yl)propane-1,2-diyldiacetate

3-((2R,3S,3aS,7R,8aR,9S,9aR)-9-acetoxy-3-hydroxy-4a-methoxy-7-(2-(pivaloyloxy)ethyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-2-yl)propane-1,2-diyldiacetate(9.5 g, 16.5 mmol) was dissolved in dichloromethane (95 mL, 1480 mmol)at ambient temperature. Imidazole (3.49 g, 51.3 mmol),diisopropylchlorosilane (5.64 mL, 33.1 mmol), and4-dimethylaminopyridine (0.202 g, 1.65 mmol) were added. After beingstirred for 2 h at ambient temperature, the reaction was quenched withsaturated aqueous NH₄Cl (27 wt %) (95 mL). The resulting mixture wasextracted with MTBE (143 mL), and the organic layer was washed with 30%aqueous NaCl (47.5 mL) and dried over MgSO₄. Filtration, concentrationin vacuo, and purification by silica gel column chromatography using 180g silica gel pretreated with n-heptane/EtOAc/TEA (500/50/1 mL) provided9.5 g of the target product as a colorless oil. ¹H NMR (3:1diastereomeric mixture, 400 MHz, CDCl₃) δ ppm 0.99-1.10 (m, 14 H) 1.18(s, 9 H) 1.44-2.00 (m, 7 H) 2.01-2.07 (m, 9 H) 2.08-2.19 (m, 1 H) 3.26(s, 3 H) 3.33-3.43 (m, 1 H) 3.72 (t, J=3.2 Hz, 1 H(minor)) 3.76 (t,J=3.8 Hz, 1 H(major)) 3.98-4.19 (m, 5 H) 4.28 (s, 1 H) 4.35 (dd, J=12.2,2.8 Hz, 1 H) 4.47 (dd, J=6.9, 4.5 Hz, 1 H) 4.96 (t, J=2.9 Hz, 1H(minor)) 5.01 (t, J=3.4 Hz, 1 H(major)) 5.12-5.32 (m, 1 H)

3-((2R,3S,3aR,7R,8aS,9R,9aR)-9-acetoxy-3-((fluorodiisopropylsilyl)oxy)-7-(2-(pivaloyloxy)ethyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-2-yl)propane-1,2-diyldiacetate

3-((2R,3S,3aR,7R,8aR,9S,9aR)-9-acetoxy-3-((diisopropylsilyl)oxy)-4a-methoxy-7-(2-(pivaloyloxy)ethyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-2-yl)propane-1,2-diyldiacetate(9.50 g, 13.8 mmol) was dissolved in dichloromethane (143 mL, 2215 mmol)and cooled below −25° C. BF₃.OEt₂ (2.55 mL, 20.7 mmol) was added, andthe resulting pale yellow solution was stirred for 5 h while warming to−10° C. Saturated aqueous NaHCO₃ (8%) (95 mL) and dichloromethane (47.5mL) were added. The layers were separated, and the aqueous layer wasextracted with dichloromethane (28.5 mL). The combined organic layerswere washed with 30% aqueous NaCl (47.5 mL) and dried over MgSO₄.Concentration in vacuo and purification by silica gel columnchromatography using a 20-100% gradient of ethyl acetate in n-heptane aseluent provided 5.24 g of the target product.

¹H NMR (4:1 diastereomeric mixture, 400 MHz, CDCl₃) δ ppm 1.12-1.16 (m,14 H) 1.18 (s, 9 H) 1.23-1.47 (m, 2 H) 1.64-1.77 (m, 3 H) 1.78-1.88 (m,1 H) 1.91-2.03 (m, 2 H) 2.04 (s, 3 H) 2.05 (s, 3 H) 2.09 (s, 3 H) 2.92(dd, J=10.3, 9.4 Hz, 1 H) 3.29-3.40 (m, 1 H) 3.84-3.97 (m, 2 H)3.98-4.19 (m, 4 H) 4.29 (dd, J=12.0, 3.2 Hz, 1 H) 4.38-4.49 (m, 2 H)5.13-5.25 (m, 1 H) 5.32 (dd, J=10.5, 7.9 Hz, 1 H).

2-((2R,3S,3aR,4aS,7R,8aR,9R,9aS)-2-(2,3-dihydroxypropyl)-3-((diisopropyl(methoxy)silyl)oxy)-9-hydroxydecahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethylpivalate

3-((2R,3S,3aR,4aS,7R,8aS,9R,9aR)-9-acetoxy-3-((fluorodiisopropylsilyl)oxy)-7-(2-(pivaloyloxy)ethyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-2-yl)propane-1,2-diyldiacetate(297 mg, 0.439 mmol) was dissolved in methanol (4.46 mL) at ambienttemperature. 0.5 M Magnesium methoxide in MeOH (1.573 mL, 0.878 mmol)was added and the resulting solution was stirred overnight. Additionalthe magnesium methoxide solution (0.5 M, 1.57 mL, 0.878 mmol) was added,and the resulting solution was stirred at ambient temperature for 10 hbefore quenching by saturated aqueous NH₄Cl (27 wt %) (5.0 mL). EtOAc(10 mL) and water (2.0 mL) were added, and the resulting white mixturewas stirred at ambient temperature for 20 min. The layers wereseparated, and the aqueous layer was extracted twice with EtOAc (16 mL).The combined organic layers were washed twice with 30% aqueous NaCl (4.0mL) and dried over MgSO₄. Filtration and concentration in vacuo provided0.211 g of the target product as an off-white foam solid.

2-((2R,3S,3aR,4aS,7R,8aR,9R,9aS)-3-((diisopropyl(methoxy)silyl)oxy)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-9-hydroxydecahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethylpivalate

2-((2R,3S,3aR,4aS,7R,8aR,9R,9aS)-2-(2,3-dihydroxypropyl)-3-((diisopropyl(methoxy)silyl)oxy)-9-hydroxydecahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethylpivalate (0.190 g, 0.338 mmol) was dissolved in acetone (2.280 mL).2,2-Dimethoxypropane (0.570 mL, 4.641 mmol) and pyridiniump-toluenesulfonate (0.017 g, 0.068 mmol) were added. The resultingsolution was stirred at ambient temperature over 1 h and treated withsaturated aqueous NaHCO₃ (8%) (3.80 mL). The resulting mixture wasextracted twice with MTBE (10 mL), and the combined organic layers werewashed with 30% aqueous NaCl (1.900 mL, 33.299 mmol) and dried overMgSO₄. Filtration and concentration gave 0.214 g of the target product.

2-((2R,3S,3aR,4aS,7R,8aS,9aR)-3-((diisopropyl(methoxy)silyl)oxy)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-9-oxodecahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethylpivalate

2-((2R,3S,3aR,4aS,7R,8aR,9R,9aS)-3-((Diisopropyl(methoxy)silyl)oxy)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-9-hydroxydecahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethylpivalate (0.214 g) was dissolved in dichloromethane (4.07 mL). Sodiumbicarbonate (0.113 g, 1.349 mmol) and Dess-Martin periodinane (0.286 g,0.674 mmol) were added. After being stirred at ambient temperatureovernight, the reaction mixture was diluted with MTBE (10.17 mL, 85.34mmol) and water (4.07 mL, 225.7 mmol). A saturated aqueous NaHCO₃ (8%)(2.033 mL) and sodium thiosulfate (0.213 g, 1.349 mmol) were then added,and the resulting mixture was stirred at ambient temperature for 30 min.The layers were separated, and the aqueous layer was extracted with MTBE(6.10 mL). The combined organic layers were washed with 30% aqueous NaCl(2.033 mL) and dried over MgSO₄. Filtration followed by concentrationgave 206 mg of the target product.

2-((2R,3S,3aR,4aS,7R,8aR,9S,9aS)-3-((diisopropyl(methoxy)silyl)oxy)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-9-hydroxydecahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethylpivalate

2-((2R,3S,3aR,4aS,7R,8aS,9aR)-3-((diisopropyl(methoxy)silyl)oxy)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-9-oxodecahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethylpivalate (206 mg) was dissolved in methanol (4.04 mL) and cooled to 0°C. Sodium borohydride (0.019 g, 0.504 mmol) was then added. The reactionwas stirred for 30 min at 0° C. and quenched with saturated aqueousNH₄Cl (27 wt %) (4.0 mL). The resulting mixture was extracted twice withMTBE (8.0 mL). The combined organic layers were washed with 30% aqueousNaCl (2.0 mL) and dried over MgSO₄. Filtration followed by concentrationin vacuo provided 216 mg of the target product.

2-((2R,3S,3aS,4aS,7R,8aR,9S,9aS)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3,9-dihydroxydecahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethylpivalate

2-((2R,3S,3aR,4aS,7R,8aR,9S,9aS)-3-((diisopropyl(methoxy)silyl)oxy)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-9-hydroxydecahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethylpivalate (216 mg) was dissolved in THF (4.0 mL) at ambient temperatureand cooled below 10° C. 1.0 M TBAF in THF (0.500 mL, 0.50 mmol) wasadded. Once all starting material was consumed, saturated aqueous NH₄Cl(27 wt %) (4.0 mL) was added, and the resulting mixture was extractedtwice with MTBE (10.04 mL). The combined organic layers were washed with30% aqueous NaCl (2.0 mL) and dried over MgSO₄. Filtration followed byconcentration and purification by silica gel column chromatography usinga 33-80% gradient of ethyl acetate in n-heptane as eluent gave 117 mg ofthe target product as a white solid.

¹ H NMR (3:1 diastereomeric mixture, 400 MHz, CDCl₃) δ ppm 1.19 (s, 9 H)1.35 (s, 3 H(minor)) 1.36 (s, 3H(major)) 1.40 (s., 3 H(minor)) 1.41 (s,3 H(major)) 1.70-2.01 (m, 7 H) 2.13-2.21 (m, 1 H) 3.00 (dd, J=9.7, 2.1Hz, 1 H(major)) 3.01 (dd, J=9.7, 2.1 Hz, 1 H(minor)) 3.46-3.54 (m, 1 H)3.59 (dd, J=8.2, 7.3 Hz, 1 H(major)) 3.61 (dd, J=8.1, 7.2 Hz, 1H(minor)) 4.00-4.22 (m, 8 H) 4.22-4.31 (m, 1 H) 4.43 (dd, J=8.9, 4.5 Hz,1 H)

A co-crystal of the desired product and the C3-epimer was obtained, andthe structure was confirmed by single crystal X-ray analysis (see FIG.7).

2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2,3-dihydroxypropyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethylpivalate

2-((2R,3S,3aS,4aS,7R,8aR,9S,9aS)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3,9-dihydroxydecahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethylpivalate (110 mg, 0.24 mmol) was dissolved in DMF (2.200 mL) at ambienttemperature. Imidazole (131 mg, 1.92 mmol),tert-butyldiphenylchlorosilane (308 μl, 1.20 mmol), and4-dimethylaminopyridine (14.65 mg, 0.12 mmol) were added. The resultingmixture was stirred at 45° C. overnight. Additional imidazole (163 mg,2.40 mmol), TBDPS-Cl (308 μl, 1.199 mmol), and 4-dimethylaminopyridine(29.3 mg, 0.24 mmol) were added. After being stirred at a temperaturebetween 60 and 70° C. for 10 h, the reaction mixture was treated withMTBE (15 mL) and a saturated NH₄Cl solution (8 mL). The aqueous layerwas separated and extracted with MTBE (10 mL). The combined organiclayers were washed twice with 30% aqueous NaCl (3 mL each) and driedover MgSO₄. Filtration followed by purification by silica gel columnchromatography provided 0.75 g of2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethylpivalate of 10 wt % purity along with mono silyl ether (81 mg) and thestarting material (19 mg). The mono silyl ether (81 mg, 0.116 mmol) andthe recovered starting material (19 mg, 0.041 mmol) were dissolved indichloromethane (1.5 mL) and cooled to 0° C. 2,6-Lutidine (0.068 mL,0.581 mmol) and tert-butyldiphenylsilyl trifluoromethanesulfonate (0.097mL, 0.314 mmol) were added. After being stirred overnight at ambienttemperature, the reaction mixture was treated with saturated NH₄Clsolution (5 mL). The resulting mixture was extracted twice with MTBE (12mL). The combined organic layers were washed with 1M aqueoushydrochloric acid (3 mL), saturated NaHCO₃ (2 mL) and 30% aqueous NaCl(2 mL). Drying over MgSO₄ and concentration in vacuo provided 0.215 g ofthick oil, which was combined into the previously isolated product. Tothe combined crude product were added acetic acid (8.0 mL) and water(2.0 mL) at ambient temperature. The resulting mixture was stirred at25-30° C. overnight. Additional acetic acid (5 mL) and water (1 mL) wereadded, and the reaction mixture was stirred at a temperature between 35and 40° C. for 4 h. Concentration in vacuo followed by purification bysilica gel column chromatography using a 20-60% gradient of ethylacetate in n-heptane as eluent provided 0.171 g of the target product asa film oil. ¹ H NMR (3:1 diastereomeric mixture, 400 MHz, CDCl₃) δ ppm1.05-1.12 (m, 18 H) 1.18 (s, 9 H) 1.28-1.68 (m, 5 H) 1.82-1.93 (m, 2 H)1.95-2.10 (m, 1 H) 2.63 (d, J=4.7 Hz, 1 H(major)) 2.75 (d, J=5.6 Hz,1H(minor)) 3.00 (dd, J=9.7, 4.1 Hz, 1 H(major)) 3.15 (dd, J=10.3, 4.7Hz, 1 H(minor)) 3.23-3.30 (m, 1 H) 3.31-3.38 (m, 1 H) 3.43-3.51 (m, 1 H)3.61 (dd, J=6.7, 4.7 Hz, 1 H) 3.70 (t, J=5.0 Hz, 1 H) 3.79-3.84 (m, 1 H)3.87 (ddd, J=9.3, 6.2, 3.2 Hz, 1 H) 3.95 (t, J=6.6 Hz, 2 H) 4.06-4.14(m, 1 H) 4.23 (t, J=5.3 Hz, 1 H) 4.30 (dd, J=6.3, 5.1 Hz, 1 H(major))4.33 (dd, J=6.6, 4.2 Hz, 1 H(minor)) 7.28-7.45 (m, 12 H) 7.62-7.79 (m, 8H)

2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-oxoethyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethylpivalate

To2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2,3-dihydroxypropyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethylpivalate (143 mg, 0.16 mmol) were added THF (2.9 mL) and water (1.4 mL)at ambient temperature. The resulting mixture was cooled to 0° C. andtreated with sodium periodate (180 mg, 0.842 mmol). After being stirredat ambient temperature for 2 h, the reaction mixture was diluted withMTBE (12 mL). The mixture was washed with saturated aqueous NaHCO₃ (8%)(3.0 mL) and 30% aqueous NaCl (2.0 mL) and dried over MgSO₄. Filtrationfollowed by concentration in vacuo provided 136 mg of the targetproduct.

2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-hydroxybut-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethylpivalate

2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-oxoethyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethylpivalate (136 mg) was dissolved in THF (2.72 mL, 33.2 mmol) and cooledto −30° C. Vinyl magnesium bromide (1.0 M in THF, 0.394 mL, 0.394 mmol)was added and the resulting solution was stirred at a temperaturebetween −30 and −35° C. for 20 min. Saturated aqueous NH₄Cl (27 wt %)(4.0 mL) was added, and the resulting mixture was warmed to ambienttemperature. The mixture was extracted with MTBE (10 mL), and theorganic layer was washed with 30% aqueous NaCl (2.0 mL) and dried overMgSO₄. Filtration and concentration of the filtrate provided 129 mg ofthe target product as a white foam solid.

2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethylpivalate

2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-hydroxybut-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethylpivalate (129 mg) was dissolved in dichloromethane (3.0 mL) at ambienttemperature. Imidazole (39.4 mg, 0.579 mmol), chlorotriethylsilane(0.049 mL, 0.289 mmol), and 4-dimethylaminopyridine (0.884 mg, 7.24μmol) were added. After being stirred at ambient temperature for 2 h,the reaction was quenched with saturated aqueous NH₄Cl (27 wt %, 5.0mL). The resulting mixture was extracted with MTBE (15 mL). The organiclayer was washed with 30% aqueous NaCl (3.0 mL), dried over MgSO₄,filtered, and concentrated in vacuo to give 0.155 g of the desiredproduct as an oil.

2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethanol

2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethylpivalate (155 mg, 0.145 mmol) was dissolved in dichloromethane (2.91 mL)and cooled to −78° C. DIBAL in toluene (1.0 M, 0.724 mL, 0.724 mmol) wasadded, and the resulting solution was stirred for 1 h. Methanol (0.1 mL,2.5 mmol) and a solution of Rochelle's salt (613 mg, 2.173 mmol) inwater (2.9 mL) were added, and the resulting mixture was allowed to warmto ambient temperature. The layers were separated, and the aqueous layerwas extracted with dichloromethane (2.91 mL). The combined organiclayers were washed with 30% aqueous NaCl (1.457 mL) and dried overMgSO₄. Filtration, concentration and purification by silica gel columnchromatography using a 20-33% gradient of ethyl acetate in n-heptane aseluent provided 107 mg of the target product as a white foam. ¹H NMR(1:1 diastereomeric mixture, 400 MHz, CDCl₃) δ ppm 0.48-0.57 (m, 3 H)0.58-0.67 (m, 3 H) 0.83-0.93 (m, 4.5 H) 0.94-1.02 (m, 4.5 H) 1.06-1.18(m, 18 H) 1.28-1.72 (m, 6.5 H) 1.85-1.94 (m, 1 H) 1.95-2.04 (m, 0.5 H)2.12 (dd, J=10.3, 4.4 Hz, 1 H) 2.98 (dd, J=9.7, 3.2 Hz, 0.5 H) 3.11 (dd,J=9.7, 6.2 Hz, 0.5 H) 3.30 (t, J=5.1 Hz, 0.5 H) 3.33-3.40 (m, 0.5 H)3.41-3.57 (m, 2.5 H) 3.58-3.70 (m, 2 H) 3.84-3.90 (m, 0.5 H) 3.92-4.02(m, 0.5 H) 4.03-4.25 (m, 2.5 H) 4.32 (dd, J=5.9, 3.2 Hz, 0.5 H)4.34-4.41 (m, 0.5 H) 4.93-5.16 (m, 2 H) 5.59-5.80 (m, 1 H) 7.24-7.46 (m,12 H) 7.57-7.83 (m, 8 H).

2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)acetaldehyde

2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethanol(80 mg, 0.087 mmol) was dissolved in dichloromethane (1.60 mL, 24.9mmol) at ambient temperature. Sodium bicarbonate (36.5 mg, 0.434 mmol)and Dess-Martin periodinane (110 mg, 0.26 mmol) were added. After beingstirred for 3 h, the reaction mixture was treated with MTBE (10 mL),saturated aqueous NaHCO₃ (8%) (2.0 mL), water (1.0 mL), and sodiumthiosulfate (137 mg, 0.868 mmol). The resulting mixture was stirred atambient temperature over 30 min. The layers were separated, and theorganic layer was washed with 30% aqueous NaCl (2.0 mL) and dried overMgSO₄. Filtration, concentration, and filtration through silica gel plugwith n-Heptane/EtOAc (2/1, 20 mL) provided 76 mg of the target productas a colorless film. ¹H NMR (1:1 diastereomeric mixture, 400 MHz, CDCl₃)δ ppm 0.45-0.56 (m, 3 H) 0.56-0.65 (m, 3 H) 0.79-1.00 (m, 9 H) 1.06-1.17(m, 18 H) 1.27-1.40 (m, 4.5 H) 1.59-1.67 (m, 1 H) 1.77 (m, 0.5 H)1.85-1.99 (m, 1 H) 2.04-2.09 (m, 1 H) 2.14 (br. s., 0.5 H) 2.16-2.20 (m,0.5 H) 2.23 (dd, J=4.5, 1.9 Hz, 0.5 H) 2.30 (dd, J=7.9, 2.1 Hz, 0.5 H)2.97 (dd, J=9.7, 3.2 Hz, 0.5 H) 3.03 (m, J=9.8, 5.7 Hz, 0.5 H) 3.47 (dd,J=6.3, 4.5 Hz, 0.5 H) 3.54-3.76 (m, 2.5 H) 3.92 (dd, J=7.0, 5.6 Hz, 0.5H) 3.98-4.29 (m, 3.5 H) 4.37 (dd, J=6.2, 3.2 Hz, 1 H) 4.94 (dt, J=10.3,1.4 Hz, 0.5H) 4.99-5.07 (m, 1 H) 5.09-5.18 (m, 0.5 H) 5.58-5.78 (m, 1 H)7.27-7.44 (m, 12 H) 7.63-7.82 (m, 8 H) 9.43 (t, J=2.1 Hz, 0.5 H) 9.51(t, J=1.9 Hz, 0.5 H)

Example 2 Preparation of the Substrate for C.15-C.16 Macrocyclization(E)-3-((2R,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)acrylaldehyde

To a stirred solution of3-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)propan-1-ol(2.5 g, 2.9 mmol) in DMSO/Toluene (20/40 mL) was added IBX (4.11 g, 14.7mmol), benzoic acid (1.79 g, 14.7 mmol), and sodium bicarbonate (0.42 g,5.0 mmol) at ambient temperature. After degassing, the reaction mixturewas stirred for 6 h at 75° C. (reaction flask was wrapped withaluminum-foil to protect from light). Additional IBX (2 g after 5 h, 3 gafter 10 h) was added, and the mixture was stirred for additional 6 h at77° C. 150 mL MTBE was added, and the resulting mixture was washed twicewith saturated NaHCO₃ solution. The organic layer was dried over MgSO₄,filtered, and purified by silica gel column chromatography to give 1.5 gof the target product. ¹H NMR (400 MHz, CDCl₃) δ ppm −0.03-0.02 (m, 12H) 0.79-0.82 (m, 18 H) 1.01 (d, J=6.6 Hz, 3 H) 1.38-1.341 (m, 1 H)1.42-1.54 (m, 3 H) 1.58-1.85 (m, 4 H) 1.90-1.95 (m, 1 H) 1.97-2.16 (m, 3H) 2.35-2.45 (m, 2 H) 2.46-2.49 (m, 2 H) 2.76-2.81 (m, 1 H) 2.91-3.00(m, 2 H) 3.34 (s, 3 H) 3.35-3.42 (m, 2 H) 3.46-3.62 (m, 2 H) 3.56-3.62(m, 1 H) 3.65-3.68 (m, 2 H) 3.70-3.77 (m, 2 H) 4.07-4.28 (m, 1 H)4.66-4.70 (m, 2 H) 4.78 (br s, 1 H) 4.84-4.90 (m, 1 H) 6.17 (ddd,J=15.6, 7.8, 1.6 Hz, 1H) 6.70 (dd, J=15.6, 4.6 Hz, 1H) 7.50-7.55 (m, 2H) 7.60-7.64 (m, 1 H) 7.87 (d, J=9.9 Hz, 2 H) 9.49 (d, J=7.8 Hz, 1 H)

(E)-3-((2R,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)prop-2-en-1-ol

(E)-3-((2R,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)acrylaldehyde(3.4 g) was dissolved in THF (70 mL) and cooled to −70° C. DIBAL intoluene (1.0 M, 5.42 mL) was added at this temperature, and theresulting solution was slowly warmed to −50° C. over a period of 2 h. Atthis time, the reaction was quenched with methanol, followed by theaddition of aqueous ammonium chloride and MTBE. The resulting mixturewas stirred for 2 h at room temperature. Extractive workup of thismixture furnished a crude product, which was purified by flash silicagel chromatography with hexanes/ethyl acetate (3:1 to 1:1) as eluent toafford 2.4 g of the desired product as an oil. ¹H NMR (400 MHz, CDCl₃) δppm −0.03-0.05 (m, 12 H) 0.80-0.86 (m, 18 H) 0.94-1.03 (m, 4 H)1.31-1.41 (m, 2 H) 1.42-1.53 (m, 3 H) 1.61-1.88 (m, 3 H) 1.92-1.98 (m, 2H) 2.10-2.17 (m, 2 H) 2.20-2.33 (m, 1 H) 2.46-2.49 (m, 1 H) 2.50-2.66(m, 1 H) 2.92-3.01 (m, 2 H) 3.38 (s, 3 H) 3.39-3.43 (m, 2 H) 3.47-3.59(m, 1 H) 3.61-3.63 (m, 1 H) 3.64-3.78 (m, 3 H) 4.07-4.08 (m, 1 H)4.02-4.05 (m, 1H) 4.36-4.41 (m, 1 H) 4.60-4.63 (br s, 1 H) 4.71 (br s, 1H) 4.85-4.89 (m, 1 H) 5.62-5.68 (m, 1 H) 5.79-5.81 (m, 1H) 7.52-7.56 (m,2 H) 7.60-7.64 (m, 1 H) 7.87-7.89 (m, 1 H).

(S)-5-(((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane

To a solution of(E)-3-((2R,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)prop-2-en-1-ol(0.42 g, 0.50 mmol) in dry THF (5 mL) at 5° C. was added sodium hydride(60% in oil, 30 mg, 0.74 mmol)), and the resulting slurry was aged atambient temperature for 20 min. Allyl bromide (0.060 mL, 0.69 mmol) andTBAI (0.018 mg, 0.049 mmol) were added. The resulting mixture wasstirred for 16 h at ambient temperature. The reaction was quenched byaddition of saturated aqueous NH₄Cl. Extraction with ethyl acetate,concentration in vacuo, and purification by silica gel columnchromatography gave 0.28 g of the target product as an oil.

¹ H NMR (400 MHz, CDCl₃) δ ppm 0.037 (s, 3 H) 0.044 (s, 3 H) 0.09 (s, 3H) 0.10 (s, 3 H) 0.87-0.89 (m, 18 H) 1.06 (d, J=6.6 Hz, 3 H) 1.22-1.32(m, 1 H) 1.37-1.48 (m, 2 H) 1.52-1.62 (m, 2 H) 1.71-1.78 (m, 1 H)1.79-1.93 (m, 2 H) 1.96-2.07 (m, 1 H) 2.13-2.26 (m, 2 H) 2.31-2.42 (m, 1H) 2.52-2.60 (m, 1 H) 2.63-2.74 (m, 1 H) 2.96-3.08 (m, 2 H) 3.35-3.41(m, 1 H) 3.43 (s, 3 H) 3.48 (m, J=5.5 Hz, 1 H) 3.54-3.62 (m, 2 H)3.64-3.71 (m, 1 H) 3.76-3.87 (m, 3 H) 3.94-4.00 (m, 4 H) 4.26-4.34 (m, 1H) 4.43 (q, J=6.6 Hz, 1 H) 4.63-4.72 (m, 1 H) 4.77 (d, J=1.6 Hz, 1 H)4.85 (s, 1 H) 4.89-4.96 (m, 1 H) 5.17 (dq, J=10.5, 1.3 Hz, 1 H) 5.27(dq, J=17.2, 1.6 Hz, 1 H) 5.65-5.82 (m, 2 H) 5.84-5.98 (m, 1 H) 7.61 (d,J=7.8 Hz, 2 H) 7.65-7.73 (m, 1 H) 7.90-8.01 (m, 2 H).

(1S)-1-((2S,3S,4R,5R)-2-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxytetrahydrofuran-3-yl)-3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-1-(phenylsulfonyl)propan-2-ol

2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)acetaldehyde(76 mg, 0.083 mmol) was dissolved in THF (0.760 mL, 9.275 mmol) andcooled to 0° C. n-Butyl lithium (1.6 M, 0.108 mL, 0.174 mmol) was added,and the resulting solution was stirred at 0° C. for 30 min and thencooled to −78° C. A solution of(S)-5-(((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane(147 mg, 0.165 mmol) in n-hexane (1.52 mL) was added, and the reactionmixture was stirred at −78° C. for 1 h. Saturated aqueous NH₄Cl (27 wt%) (3.0 mL), water (1.0 mL), and MTBE (8.0 mL) were added, and theresulting mixture was warmed up to ambient temperature. The organiclayer was separated, washed with 30% aqueous NaCl (2.0 mL), and driedover MgSO₄. Filtration, concentration in vacuo, and purification bysilica gel column chromatography using a 20-50% gradient of ethylacetate in n-heptane as eluent provided 152 mg of the target product.

(1S)-1-((2S,3S,4R,5R)-2-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxytetrahydrofuran-3-yl)-3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-1-(phenylsulfonyl)propan-2-one

(1S)-1-((2S,3S,4R,5R)-2-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxytetrahydrofuran-3-yl)-3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-1-(phenylsulfonyl)propan-2-ol(152 mg, 0.084 mmol) was dissolved in dichloromethane (3.04 mL) atambient temperature. Sodium bicarbonate (35.3 mg, 0.42 mmol) andDess-Martin periodinane (89 mg, 0.21 mmol) were added, and the resultingmixture was stirred at ambient temperature overnight. MTBE (7.600 mL),water (1.52 mL), saturated aqueous NaHCO₃ (8%) (3.04 mL), and sodiumthiosulfate (133 mg, 0.84 mmol) were added. After stirring at ambienttemperature for 1 h, the layers were separated. The organic layer waswashed with 30% aqueous NaCl (3.0 mL) and dried over MgSO₄. Filtration,concentration, and purification by silica gel column chromatographyusing a 12-25% gradient of ethyl acetate in n-heptane as eluent provided77 mg of the target product.

1-((2S,3S,4R,5R)-2-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxytetrahydrofuran-3-yl)-3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)propan-2-one

(1S)-1-((2S,3S,4R,5R)-2-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxytetrahydrofuran-3-yl)-3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-1-(phenylsulfonyl)propan-2-one(77 mg) was dissolved in THF (1.2 mL) and MeOH (0.77 mL). The resultingsolution was cooled to −78° C. and treated with 0.1M samarium diiodide(1.28 mL, 0.128 mmol) for 1 h. The reaction was quenched with a mixtureof Rochelle's salt (385 mg, 1.36 mmol), potassium carbonate (385 mg,2.79 mmol), and water (3.85 mL). MTBE (5.0 mL) was added, and theresulting mixture was warmed to ambient temperature. The layers wereseparated, and the aqueous layer was extracted with MTBE (5.0 mL). Thecombined organic layers were washed with 30% aqueous NaCl (2.0 mL) anddried over MgSO₄. Filtration, concentration, and purification by silicagel column chromatography using a 25-33% gradient of ethyl acetate inn-heptane as eluent provided 46 mg of the target product. ¹H NMR (1:1diastereomeric mixture, 400 MHz, CDCl₃) δ ppm −0.01-0.13 (m, 12 H)0.46-0.65 (m, 6 H) 0.84-0.99 (m, 27 H) 1.02-1.16 (m, 21 H) 1.22-1.36 (m,1 H) 1.45-1.82 (m, 10 H) 1.87-2.29 (m, 9 H) 2.32-2.45 (m, 2 H) 2.65-2.77(m, 1 H) 2.98 (dd, J=9.5, 3.1 Hz, 0.5 H) 3.04 (dd, J=9.7, 5.3 Hz, 0.5 H)3.20 (t, J=4.0 Hz, 1 H) 3.30 (s, 1.5H) 3.34 (m, 1.5 H) 3.39-3.90 (m, 12H) 3.92-4.03 (m, 4 H) 4.06-4.24 (m, 3 H) 4.31-4.39 (m, 1 H) 4.39-4.51(m, 2 H) 4.73-4.86 (m, 3 H) 4.91-5.06 (m, 3 H) 5.16 (d, J=1.2 Hz, 1 H)5.22-5.30 (m, 1 H) 5.58-5.82 (m, 3 H) 5.84-5.97 (m, 1 H) 7.26-7.43 (m,12 H) 7.62-7.80 (m, 8 H)

Example 3 Preparation of a Compound of Formula (ID) Through C.15-C.16Macrocyclization

1-((2S,3S,4R,5R)-2-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxytetrahydrofuran-3-yl)-3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)propan-2-one(32 mg, 0.019 mmol) was dissolved in toluene (7.0 mL). Hoveyda-Grubbs2^(nd) generation catalyst (1.448 mg, 2.304 μmol) was added, and theresulting solution was heated to 70° C. After being stirred at 70° C.overnight, the reaction mixture was cooled to ambient temperature andconcentrated in vacuo. Silica gel column chromatography of the residueusing a 10-50% gradient of ethyl acetate in n-heptane as eluent afforded9.3 mg of the target product. MS m/z 1591.1 [M+Na]⁺. ¹ H NMR (1.5:1diastereomeric mixture, 400 MHz, CDCl₃) δ ppm 0.01-0.10 (m, 12 H) 0.58(td, J=7.8, 5.7 Hz, 6 H) 0.81-0.97 (m, 30 H) 1.00-1.12 (m, 18 H)1.17-2.80 (m, 24 H) 2.88 (t, J=9.1 Hz, 1 H(major)) 2.97 (t, J=9.4 Hz,1H(minor)) 3.29-3.35 (m, 1 H) 3.37 (s, 3 H(major)) 3.42 (s, 3 H(minor))3.42-3.85 (m, 10H), 3.96-4.15 (m, 3 H) 4.34 (m, 2 H) 4.40-4.48 (m, 1 H)4.54-4.70 (m, 1H) 4.78-4.82 (m, 1 H) 4.85 (br. s., 1 H) 4.90-4.92 (m, 1H) 4.96-5.01 (m, 1 H) 5.51 (dd, J=15.2, 7.0 Hz, 1 H(minor)) 5.81 (ddd,J=15.4, 7.6, 1.3 Hz, 1 H(major)) 6.32 (dd, J=15.2, 3.5 Hz, 1 H(major))6.59 (dd, J=15.4, 8.9 Hz, 1 H(minor)) 7.28-7.45 (m, 12 H) 7.52-7.78 (m,8 H)

Compound 1 (4.6 mg, 2.9 μmol) was dissolved in THF (1.1 mL) at ambienttemperature. To the solution was added acetic acid (0.5 mL) and water(0.3 mL). After being stirred for 3 h at ambient temperature, theresulting mixture was concentrated in vacuo. The residue was purified bysilica gel column chromatography using a 10-33% gradient of ethylacetate in n-heptane as eluent to give 4.0 mg of compound 2. ¹H NMR(major isomer, 400 MHz, CDCl₃) δ ppm −0.02-0.09 (m, 12 H) 0.88 (s, 9 H)0.89 (s, 9 H) 1.03 (s, 9 H) 1.05 (d, J=6.4 Hz, 3 H) 1.07 (s, 9 H)1.25-2.81 (m, 24 H) 2.95 (t, J=9.1 Hz, 1 H) 3.33 (d, J=3.5 Hz, 1 H) 3.40(s, 3 H) 3.44-3.53 (m, 2 H) 3.53-3.61 (m, 2 H) 3.66-3.85 (m, 8 H) 4.08(dd, J=8.6, 3.7 Hz, 1 H) 4.29-4.40 (m, 2 H) 4.42-4.48 (m, 1 H) 4.60-4.69(m, 2 H) 4.79 (s, 1 H) 4.86 (br. s., 1 H) 4.90 (s, 1 H) 4.99 (br. s., 1H) 5.79 (ddd, J=15.7, 7.9, 1.6 Hz, 1 H) 6.54 (dd, J=15.4, 3.7 Hz, 1 H)7.28-7.45 (m, 12 H) 7.52-7.76 (m, 8 H)

Compound 2 (4.0 mg, 2.751 μmol) was dissolved in dichloromethane (1.0mL) at ambient temperature. Sodium bicarbonate (1.4 mg, 0.017 mmol) andDess-Martin periodinane (3.5 mg, 8.3 μmol) were added, and the resultingmixture was stirred at ambient temperature overnight. MTBE (3.0 mL),water (1.0 mL), saturated aqueous NaHCO₃ (8%) (1.0 mL), and sodiumthiosulfate (2.174 mg, 0.014 mmol) were added. The resulting mixture wasstirred at ambient temperature over 30 min. The organic layer wasseparated, washed with 30% aqueous NaCl (0.5 mL) and dried over MgSO₄.Filtration followed by concentration in vacuo provided 3.3 mg ofcompound 3.

Compound 3 (3.3 mg, 2.3 μmol) was dissolved in deoxygenated toluene (0.5mL) at ambient temperature. Deoxygenated (purged with nitrogen for 40min) water (2 μl, 0.11 mmol) followed by Stryker's reagent (4.5 mg, 2.3μmol) was added. After 1 h, additional Stryker's reagent (˜2 mg) wasadded. After being stirred for additional 1 h, the reaction mixture wastreated with air. A precipitate formed. Concentration followed bypurification by column chromatography using a 10-20% gradient of ethylacetate in n-heptane as eluent afforded 2.5 mg of compound 4.

¹H NMR (400 MHz, CDCl₃) δ ppm 0.03-0.10 (m, 12 H) 0.88 (s, 9 H) 0.90 (s,9 H) 1.00 (s, 9 H) 1.05 (d, J=6.4 Hz, 3 H) 1.08 (s, 9 H) 1.20-2.20 (m,21 H) 2.25-2.35 (m, 1 H) 2.46-2.81 (m, 6H) 2.90-2.99 (m, 1 H) 3.05 (t,J=11.7 Hz, 1 H) 3.09 (t, J=9.1 Hz, 1 H) 3.32 (d, J=2.3 Hz, 1 H) 3.42 (s,3 H) 3.48 (dd, J=4.5, 3.7 Hz, 1 H) 3.51 (dd, J=10.5, 5.0 Hz, 1 H) 3.58(dd, J=10.4, 5.7 Hz, 1 H) 3.69-3.92 (m, 7 H) 4.05 (dd, J=8.8, 3.2 Hz, 1H) 4.11-4.20 (m, 1 H) 4.35 (m, 1 H) 4.37-4.44 (m, 1 H) 4.78 (s, 1 H)4.86 (d, J=1.5 Hz, 1 H) 4.90 (s, 1 H) 4.98 (d, J=1.8 Hz, 1 H) 7.27-7.46(m, 12 H) 7.58-7.69 (m, 8 H)

To compound 4 (2.5 mg, 1.719 μmol) in a vial was added THF (230 μl) andN,N-dimethylacetamide (88 μl) at ambient temperature. A mixture of TBAF(34 μl, 0.034 mmol) and imidazole hydrochloride (1.8 mg, 0.017 mmol) wasadded, and the resulting mixture was stirred over 20 h at ambienttemperature. A mixture of acetonitrile (60 μL) and water (20 μL) wasadded, and the resulting mixture was stirred at ambient temperature for2 days. 30% aqueous NaCl (0.13 mL) and toluene (0.7 mL) were added. Thelayers were separated, and the aqueous layer was extracted twice with amixture of THF (1.4 mL) and toluene (1.4 mL). The combined organic layerwas concentrated under a stream of nitrogen. The residue was dissolvedin dichloromethane (0.2 mL) at ambient temperature, and PPTS (0.80 mg,3.2 μmol) was added. After 1 h and after 4 h, additional PPTS (0.4 mgand 3 mg, respectively) was added. Once all starting material wasconsumed, the reaction mixture was purified by silica gel columnchromatography using heptane/ethyl acetate (1/1), ethyl acetate, andMTBE/MeCN (1/1) as eluent to give 1.6 mg of compound 6. The structurewas confirmed by comparison of the ¹H NMR spectrum with the reportedspectrum.

¹H NMR (500 MHz, methanol-d₄) δ ppm 1.01-1.10 (m, 2 H) 1.14 (d, J=6.6Hz, 3 H) 1.30-1.64 (m, 7 H) 1.70-2.54 (m, 17 H) 2.67-2.81 (m, 2 H)2.87-2.94 (m, 1 H) 2.96-2.98 (m, 1 H) 3.38-3.41 (m, 1 H) 3.45 (s, 3 H)3.50 (dd, J=11.4, 6.2 Hz, 1 H) 3.54 (dd, J=11.0, 4.4 Hz, 1 H) 3.69-3.80(m, 2 H) 3.84-3.94 (m, 3 H) 4.01 (t, J=10.6 Hz, 1 H) 4.10-4.18 (m, 2 H)4.21 (dd, J=6.4, 4.6 Hz, 1 H) 4.27-4.39 (m, 2 H) 4.51 (d, J=10.6 Hz, 1H) 4.64 (t, J=4.4 Hz, 1 H) 4.74 (t, J=4.6 Hz, 1 H) 4.86 (br. s., 1 H)4.92 (s, 1 H) 5.06 (s, 1 H) 5.17 (d, J=1.8 Hz, 1 H)

(S)-3-((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1,2-diol

To a stirred solution of(S)-5-(((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane(3.8 g, 4.27 mmol) in THF (50 mL) at 5° C. was added 1M THF solution ofTBAF (12.8 mL, 12.8 mmol). The reaction was warmed to room temperature.After aging for 16 h at this temperature, the reaction was quenched byaddition of aqueous ammonium chloride (10 mL). After dilution with ethylacetate (30 mL), the phases were separated. The aqueous layer wasback-extracted with ethyl acetate (2×50 mL), and the organic layers werecombined. The combined organic layers were dried over MgSO₄. Removal ofthe solvent under reduced pressure and flash silica gel chromatographyof the residue with heptanes-ethyl acetate (2:1 to 1:2) as eluentafforded 2.3 g (81%) of desired product as an oil.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.34-1.41 (m, 2 H) 1.47-1.54 (m, 4 H)1.67-1.77 (m, 3 H) 1.86-1.96 (m, 3 H) 2.10-2.17 (m, 2 H) 2.28-2.33 (m, 1H) 2.51-2.55 (m, 1 H) 2.56-2.66 (m, 1 H) 2.99-3.08 (m, 2 H) 3.29-3.34(m, 2 H) 3.38 (s, 3 H) 3.39-3.59 (m, 4 H) 3.73-3.78 (m, 1 H) 3.84-3.90(m, 3 H) 3.90-3.92 (m, 4 H) 4.20-4.28 (m, 1 H), 4.37-4.39 (m, 1 H)4.63-4.64 (m, 1H) 4.73 (br s, 1H), 4.78 (br s, 1 H) 4.86 (m, 1 H)5.10-5.13 (m, 1 H) 5.19-5.23 (m, 1 H) 5.66-5.73 (m, 1 H) 5.81-5.88 (m, 1H) 7.53-7.57 (m, 2 H) 7.62-7.67 (m, 1 H) 7.86-7.90 (m, 2 H).

(S)-1-((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)-3-aminopropan-2-ol

To a stirred solution of(S)-3-((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylene-tetrahydro-2H-pyran-2-yl)methyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1,2-diol(1.05 g, 1.59 mmol) in methylene chloride (30 mL) was added2,4,6-collidine (0.84 mL, 6.35 mmol) and pyridine (7 μl, 0.08 mmol). Theresulting mixture was cooled to −10° C., and Ts₂O (1.1 g, 1.75 mmol) wasadded in two portions. The reaction was stirred for 3 h at a temperaturebetween −10 and −5° C. and at 0° C. for 2 h. The reaction then waswarmed to room temperature, and isopropanol (75 mL) and ammoniumhydroxide (85 mL) were added. After aging 16 h at room temperature,additional ammonium hydroxide (20 ml) was added, and stirring wascontinued for 6 h at a temperature between 26 and 30° C. After removalof organic solvents under reduced pressure, the residue was extractedwith methylene chloride (3×40 mL). The combined organic layers werewashed with brine and dried over MgSO₄. Removal of the solvent andsilica gel chromatography of the residue with hexanes/ethyl acetate (2:1to pure ethyl acetate) as eluent afforded the desired product as a foam.Since the product was contaminated with small amount of 2,4,6-collidine,it was further purified by precipitation of product from cyclohexane orn-heptane (740 mg, 70.6%). ¹H NMR (400 MHz, CDCl₃) δ ppm 0.95-1.11 (m, 3H) 1.22-1.37 (m, 2 H) 1.46-1.50 (m, 2 H) 1.78-1.84 (m, 3 H) 2.04-2.19(m, 3 H) 2.26-2.37 (m, 2 H) 2.50-2.59 (m, 2 H) 2.63-2.90 (m, 2 H)2.92-3.04 (m, 2 H) 3.12-3.22 (m, 1 H) 3.26 (s, 3 H) 3.36-3.39 (m, 2 H)3.44-3.49 (m, 1 H) 3.54-3.56 (m, 1 H) 3.60-3.68 (m, 1 H) 3.78-3.94 (m, 4H), 4.03-4.06 (m, 1 H) 4.07-4.19 (m, 1 H) 4.36-4.38 (m, 1 H), 4.58-4.86(m, 4 H) 5.08-5.16 (m, 2 H) 5.63-5.68 (m, 2 H) 5.66-5.83 (m, 1H)7.48-7.62 (m, 3 H) 7.84-7.89 (m, 2 H).

tert-butyl((S)-3-((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)-2-hydroxypropyl)carbamate

To a stirred solution of(S)-1-((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylene-tetrahydro-2H-pyran-2-yl)methyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)-3-aminopropan-2-ol(0.7 g, 1.06 mmol) and triethylamine (0.22 mL, 1.6 mmol) in methylenechloride (20 mL) was added di-tert-butyl dicarbonate (290 mg, 1.34 mmol)at room temperature. The mixture was aged for 14 h at room temperatureunder nitrogen with a vent for CO₂ release. After quenching with aq. satammonium chloride (15 ml), phases were separated. The aqueous layer wasextracted with methylene chloride (15 mL), and the combined organiclayers were washed with brine and concentrated to dryness. The resultingcrude product was purified by silica gel column chromatography usinghexanes-ethyl acetate (3:1 to 1:1) to give the product as an oil (0.6 g,74%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.15-1.25 (m, 7 H) 1.30-1.42 (m, 2H) 1.37 (br s, 9 H) 1.43-1.56 (m, 3 H) 1.67-1.72 (m, 2 H) 1.81-1.93 (m,2 H) 2.09-2.19 (m, 2 H) 2.27-2.33 (m, 1 H) 2.40-2.50 (m, 1 H) 2.51-2.59(m, 1 H) 2.61-2.65 (m, 1 H) 3.00-3.10 (m, 2 H) 3.20-3.30 (m, 1 H)3.33-3.39 (m, 1 H) 3.36 (s, 3 H) 3.51-3.53 (m, 1 H) 3.65-3.74 (m, 1 H)3.79-3.86 (m, 2 H) 3.90-3.91 (m, 3 H) 4.24-4.34 (m, 1 H) 4.36-4.38 (m, 1H) 4.62 (d, J=1.9 Hz 1 H) 4.72 (br s, 1 H) 4.77 (br s, 1 H) 4.85 (d,J=1.9 Hz, 1 H) 4.93 (br s, 1 H) 5.12 (dd, J=10.5, 1.5 Hz, 1 H),5.18-5.23 (m, 1H) 5.65-5.72 (m, 2 H) 5.80-5.87 (m, 1 H) 7.52-7.56 (m, 2H) 7.61-7.65 (m, 1 H) 7.845-7.89 (m, 2 H).

(S)-tert-butyl5-(((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate

To a stirred solution of tert-butyl((S)-3-((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylene-tetrahydro-2H-pyran-2-yl)methyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)-2-hydroxypropyl)carbamate(0.50 g, 0.66 mmol) in acetone (10 mL) was added 2,2-dimethoxypropane(1.0 mL, 8.16 mmol) and p-toluenesulfonic acid monohydrate (15 mg, 0.08mmol). The reaction mixture was stirred for 1.5 h at room temperature.After adding sodium bicarbonate (200 mg), the reaction was stirred foradditional 10 min. After dilution with ethyl acetate (40 mL) andsaturated aqueous NaHCO₃ (20 mL), the resulting mixture was phaseseparated. The organic layer was back-extracted with ethyl acetate (25mL). The combined organic layers were washed with brine and concentratedto dryness. The resulting crude product was further purified by silicagel column chromatography using a gradient from 4:1 to 2:1 ofheptanes/ethyl acetate as eluent to give 400 mg of the desired productas an oil (76%). ¹H NMR (400 MHz, CDCl₃)δ ppm 1.15-1.29 (m, 4 H) 1.3-1.5(m, 4 H), 1.40 (br s 9 H) 1.49 (s, 6 H) 1.66-1.69 (m, 1 H) 1.78-1.83 (m,1 H) 1.89-1.98 (m, 1 H) 2.03-2.12 (m, 3 H) 2.27-2.32 (m, 1 H) 2.51-2.59(m, 1 H) 2.61-2.64 (m, 1 H) 2.97-3.08 (m, 3 H) 3.20-3.33 (m, 1 H) 3.37(s, 3 H) 3.46-3.53 (m, 1 H) 3.61-3.67 (m, 3 H) 3.80-3.91 (m, 4 H)4.07-4.11 (m, 1 H) 4.20-4.25 (m, 1 H) 4.34-4.37 (m, 1 H) 4.65 (d, d=2.0Hz, 1 H) 4.71 (br s, 1 H) 4.78 (br s, 1 H) 4.84 (d J=2.0 Hz, 1 H)5.10-5.23 (m, 2 H) 5.61-5.72 (m, 2 H) 5.80-5.87 (m, 1 H) 7.53-7.57 (m, 2H) 7.61-7.65 (m, 1 H) 7.89-7.90 (m, 2 H).

1-((5S)-5-(((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-4-((1S)-3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-2-hydroxy-1-(phenylsulfonyl)propyl)-3-methoxytetrahydrofuran-2-yl)methyl)-2,2-dimethyloxazolidin-3-yl)-2,2-dimethylpropan-1-one

2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)acetaldehyde(100 mg, 0.109 mmol) was dissolved in THF (1.0 mL) and cooled to 0° C.n-Butyl lithium (1.6 M, 0.109 mL, 0.174 mmol) was added, and theresulting solution was stirred at 0° C. for 30 min and then cooled to−78° C. A solution of1-((S)-5-(((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-2,2-dimethyloxazolidin-3-yl)-2,2-dimethylpropan-1-one(0.128 g, 0.163 mmol) in n-heptane (2.0 mL), and the reaction mixturewas stirred at −78° C. for 1 h. Saturated aqueous NH₄Cl (27 wt %) (4.0mL), water (1.3 mL), and MTBE (10.5 mL) were added, and the resultingmixture was warmed to ambient temperature. The organic layer wasseparated, washed with 30% aqueous NaCl (2.6 mL), and dried over MgSO₄.Filtration, concentration in vacuo, and purification by silica gelcolumn chromatography using a 20-66% gradient of ethyl acetate inn-heptane as eluent provided 142 mg of the target product.

(5S)-tert-butyl5-(((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-4-((1S)-3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-2-oxo-1-(phenylsulfonyl)propyl)-3-methoxytetrahydrofuran-2-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate

(5S)-tert-butyl5-(((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-4-((1S)-3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-2-hydroxy-1-(phenylsulfonyl)propyl)-3-methoxytetrahydrofuran-2-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate(0.142 g, 0.083 mmol) was dissolved in dichloromethane (5.0 mL) atambient temperature. Sodium bicarbonate (35 mg, 0.41 mmol) andDess-Martin periodinane (105 mg, 0.248 mmol) were added, and theresulting mixture was stirred at ambient temperature overnight. MTBE(14.2 mL), water (7.1 mL), and sodium thiosulfate (131 mg, 0.83 mmol)were added. After stirring at ambient temperature for 1 h, the layerswere separated. The organic layer was washed with saturated aqueousNaHCO3 (8%) (2.84 mL), 30% aqueous NaCl (2.8 mL) and dried over MgSO₄.Filtration, concentration, and filtration through silica gel plug, whichwas then rinsed with 33% ethyl acetate in n-heptane, provided 120 mg ofthe target product as a colorless film.

(5S)-tert-butyl5-(((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-4-(3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-2-oxopropyl)-3-methoxytetrahydrofuran-2-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate

(5S)-tert-butyl5-(((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-4-((1S)-3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-2-oxo-1-(phenylsulfonyl)propyl)-3-methoxytetrahydrofuran-2-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate(0.120 g, 0.07 mmol) was dissolved in THF (1.9 mL) and MeOH (1.2 mL).The resulting solution was cooled to −78° C. and treated with 0.1 Msamarium diiodide (2.1 mL, 0.21 mmol) for 30 min. Additional 0.1 Msamarium diiodide (2.1 mL, 0.21 mmol) was added, and the resultingmixture was stirred for 30 min at −78° C. The reaction was quenched withsaturated Rochelle's salt solution (8 mL). Water (4 mL) and MTBE (7.2mL) were added, and the resulting mixture was warmed to ambienttemperature. The layers were separated, and the aqueous layer wasextracted with MTBE (7.2 mL). The combined organic layers were washedwith 30% aqueous NaCl (2.4 mL) and dried over MgSO₄. Filtration,concentration, and purification by silica gel column chromatographyusing a 20-50% gradient of ethyl acetate in n-heptane as eluent provided74 mg of the target product as a white foam. ¹H NMR (1:1 diastereomericmixture, 400 MHz, CDCl₃) δ ppm 0.45-0.65 (m, 6 H) 0.82-1.00 (m, 9 H)1.03 (d, J=7.0 Hz, 1.5 H) 1.04 (d, J=7.0 Hz, 1.5 H) 1.06-1.17 (m, 18 H)1.27-1.82 (m, 14 H) 1.47 (br. s., 12 H) 1.85-2.47 (m, 10 H) 2.67-2.77(m, 1 H) 2.95-3.07 (m, 1 H) 3.08-3.18 (m, 1 H) 3.23 (br. s., 1 H) 3.29(s, 1.5 H) 3.31 (s, 1.5 H) 3.36-3.82 (m, 10 H) 3.87 (t, J=6.3 Hz, 0.5 H)3.96 (d, J=5.5 Hz, 4 H) 3.99-4.25 (m, 5 H) 4.33 (dd, J=6.3, 3.1 Hz, 1 H)4.41 (br. s., 1 H) 4.44-4.52 (m, 1 H) 4.73-4.82 (m, 2 H) 4.83 (s, 1 H)4.91-5.15 (m, 2 H) 4.97 (d, J=2.0 Hz, 1 H) 5.16 (br. s., 0.5 H) 5.18 (s,0.5 H) 5.24 (d, J=1.6 Hz, 0.5 H) 5.28 (d, J=1.6 Hz, 0.5 H) 5.61-5.81 (m,3 H) 5.84-5.97 (m, 1 H) 7.27-7.43 (m, 12 H) 7.62-7.81 (m, 8 H)

To a solution of Hoveyda-Grubbs 2nd Generation Catalyst (11.8 mg, 0.019mmol) in toluene (50 mL) at 70° C. was added a solution of(5S)-tert-butyl5-(((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-4-(3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-2-oxopropyl)-3-methoxytetrahydrofuran-2-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate(74 mg, 0.047 mmol) in toluene (10 mL) over 4 h. After stirring at 80°C. for 10 h, the reaction mixture was cooled to ambient temperature andconcentrated in vacuo. Silica gel column chromatography of the residueusing a 10-33% gradient of ethyl acetate in n-heptane as eluent afforded35 mg of the target product. ¹H NMR (1.4:1 diastereomeric mixture, 400MHz, CDCl₃) δ ppm 0.45-0.66 (m, 6 H) 0.83-0.96 (m, 9 H) 0.99-1.16 (m, 21H) 1.27-3.03 (m, 31 H) 1.47 (br. s., 9 H) 3.10-3.20 (m, 1 H) 3.28-3.91(m, 12 H) 3.35 (s, 3 H(major)) 3.40 (s, 3 H(minor)) 3.99-4.09 (m, 1 H)4.11-4.17 (m, 1 H) 4.29-4.38 (m, 1 H) 4.41-4.49 (m, 1 H) 4.56-4.70 (m, 1H) 4.77-4.82 (m, 1 H) 4.85 (br. s., 1 H) 4.89-4.93 (m, 1 H) 4.97-5.01(m, 1 H) 5.51 (dd, J=15.4, 7.6 Hz, 1 H(minor)) 5.81 (ddd, J=15.4, 7.8,1.4 Hz, 1 H(major)) 6.33 (d, J=15.6 Hz, 1H(major)) 6.58 (dd, J=15.4, 9.2Hz, 1 H(minor)) 7.27-7.45 (m, 12 H) 7.58-7.79 (m, 8 H)

Compound 7 (35 mg, 24 μmol) was dissolved in THF (3.9 mL) at ambienttemperature. To the solution was added acetic acid (1.8 mL) and water(1.1 mL). After being stirred for 3.5 h at ambient temperature, theresulting mixture was concentrated in vacuo. The residue was purified bysilica gel column chromatography using a 20-50% gradient of ethylacetate in n-heptane as eluent to give 32 mg of compound 8.

Compound 8 (32 mg, 23 μmol) was dissolved in dichloromethane (1.9 mL) atambient temperature. Sodium bicarbonate (11.8 mg, 0.141 mmol) andDess-Martin periodinane (30 mg, 0.070 mmol) were added, and theresulting mixture was stirred at ambient temperature for 5 h. MTBE (10mL), water (5 mL), saturated aqueous NaHCO₃ (8%) (2.0 mL), and sodiumthiosulfate (56 mg, 0.35 mmol) were added. The resulting mixture wasstirred at ambient temperature over 30 min. The organic layer wasseparated, washed with 30% aqueous NaCl (2 mL) and dried over MgSO₄.Filtration followed by concentration in vacuo and purification by silicagel column chromatography using a 20-50% gradient of ethyl acetate inn-heptane as eluent provided 17 mg of compound 9 as a colorless film. ¹HNMR (400 MHz, CDCl₃) ppm 0.98 (s, 9 H) 1.04-1.10 (m, 12 H) 1.26 (br. s.,3 H) 1.29-1.84 (m, 8 H) 1.47 (br. s., 9H) 1.55 (s, 3 H) 1.90-1.98 (m, 2H) 2.03-2.11 (m, 3 H) 2.13-2.24 (m, 2 H) 2.46-2.56 (m, 3 H) 2.61 (dd,J=16.0, 7.4 Hz, 2 H) 2.74-2.83 (dd, J=16.2, 5.7 Hz, 2 H) 3.06-3.21 (m, 2H) 3.25-3.33 (m, 1 H) 3.37 (d, J=3.9 Hz, 1 H) 3.38 (s, 3 H) 3.44-3.52(m, 1 H) 3.63-3.93 (m, 8 H) 4.06 (dd, J=8.4, 3.7 Hz, 1 H) 4.12-4.21 (m,1 H) 4.35 (t, J=6.4 Hz, 1 H) 4.46-4.54 (m, 1 H) 4.70 (q, J=6.8 Hz, 1 H)4.79 (s, 1 H) 4.87-4.95 (m, 2 H) 5.03 (d, J=2.0 Hz, 1 H) 6.58 (dd,J=16.0, 7.8 Hz, 1 H) 6.79 (dd, J=16.0, 5.5 Hz, 1 H) 7.28-7.44 (m, 12 H)7.56-7.70 (m, 8 H)

Compound 10 (17 mg, 0.012 mmol) was dissolved in deoxygenated toluene(2.6 mL) at ambient temperature. Deoxygenated (purged with nitrogen for40 min) water (10 μL, 0.57 mmol) followed by Stryker's reagent (24.5 mg,12 μmol) was added. After 1 h, additional Stryker's reagent (˜20 mg) wasadded. After being stirred for additional 1 h, the reaction mixture wastreated with air. A precipitate formed. Purification by columnchromatography using a 10-50% gradient of ethyl acetate in n-heptane aseluent afforded 14.7 mg of compound 11 as a colorless film. ¹H NMR (400MHz, CDCl₃) δ ppm 1.00 (s, 9 H) 1.06 (d, J=6.3 Hz, 3 H) 1.08 (s, 9 H)1.23-1.33 (m, 6 H) 1.47 (br s, 12H), 1.50-2.00 (m, 11 H) 2.06-2.23 (m, 4H) 2.26-2.34 (m, 1 H) 2.46-2.54 (m, 1 H) 2.54-2.82 (m, 5 H) 2.89-3.00(m, 1 H) 3.03-3.12 (m, 2 H) 3.13-3.20 (m, 1 H) 3.36 (d, J=3.1 Hz, 1 H)3.41 (s, 3 H) 3.47-3.51 (m, 1 H) 3.63-3.85 (m, 7 H) 3.92 (ddd, J=10.9,7.4, 3.5 Hz, 1 H) 4.05 (dd, J=8.8, 3.3 Hz, 1 H) 4.11-4.22 (m, 2 H)4.31-4.42 (m, 2 H) 4.79 (s, 1 H) 4.85 (s, 1 H) 4.90 (s, 1 H) 4.98 (d,J=1.6 Hz, 1 H) 7.26-7.48 (m, 12 H) 7.57-7.71 (m, 8 H)

To a solution of compound 11 (14.7 mg, 10.8 μmol) in methanol (1 mL) wasadded p-toluenesulfonic acid monohydrate (2.05 mg, 10.8 μmol) at ambienttemperature. The resulting solution was stirred for 3 h and treated withsaturated aqueous NaHCO₃ (8%) (3 mL). The resulting mixture wasextracted twice with MTBE (12 mL). The combined organic layers werewashed with 30% aqueous NaCl (2 ml) and dried over MgSO₄. Filtrationfollowed by concentration in vacuo provided 14.7 mg of compound 13 ascolorless oil.

Compound 13 (14.7 mg, 10.7 μmol) was dissolved in THF (1.3 mL) andN,N-dimethylacetamide (0.5 mL) at ambient temperature. 1.0 M TBAF in THF(0.22 mL, 0.022 mmol) and imidazole hydrochloride (11.3 mg, 0.108 mmol)were added, and the resulting mixture was stirred for 20 h at ambienttemperature. 30% aqueous NaCl (2 mL) and toluene (3 mL) were added. Thelayers were separated, and the aqueous layer was extracted twice with amixture of THF (3 mL) and toluene (3 mL). The combined organic layer wasconcentrated in vacuo. The residue was dissolved in dichloromethane (1.5mL) at ambient temperature, and pyridinium p-toluenesulfonate (27 mg,0.107 mmol) was added. After 3 h, the reaction mixture was purified bysilica gel column chromatography using ethyl acetate as eluent to give6.5 mg of compound 14 as a white foam. ¹H NMR (400 MHz, CDCl₃) δ ppm1.10 (d, J=6.6 Hz, 3 H) 1.28-1.79 (m, 11 H) 1.44 (s, 9 H) 1.89-2.51 (m,15 H) 2.71 (dd, J=16.0, 10.2 Hz, 1 H) 2.85 (dd, J=6.6, 2.0 Hz, 1 H) 2.89(dd, J=7.4, 2.3 Hz, 1 H) 3.08-3.17 (m, 1 H) 3.26 (d, J=3.1 Hz, 1 H) 3.42(s, 3 H) 3.55 (br. s., 1 H) 3.58-3.66 (m, 2 H) 3.81 (dt, J=9.4, 3.3 Hz,1 H) 3.87-3.99 (m, 3 H) 4.03 (dd, J=6.3, 4.3 Hz, 1 H) 4.09-4.16 (m, 1 H)4.19 (dd, J=6.4, 4.5 Hz, 1 H) 4.29 (dd, J=10.6, 4.3 Hz, 1 H) 4.31-4.38(m, 2 H) 4.60 (t, J=4.5 Hz, 1 H) 4.69 (t, J=4.7 Hz, 1 H) 4.81 (d, J=1.2Hz, 1 H) 4.89 (s, 1 H) 4.93 (br. s, 1 H) 4.98-5.05 (m, 1 H) 5.07 (d,J=2.0 Hz, 1 H)

To a solution of compound 14 (3.2 mg, 3.9 μmol) in dichloromethane (0.5mL) at 0° C. were added 2,6-lutidine (4.9 μL, 0.042 mmol) andtrimethylsilyl trifluoromethanesulfonate (5.9 μL, 0.033 mmol) was added,and the resulting solution was warmed to ambient temperature. After 1 hand 3 h, additional 2,6-lutidine (5 μl) and trimethylsilyltrifluoromethanesulfonate (6 μl) were added each time. After additional1.5 h stirring, the reaction was quenched with water (3 mL). Theresulting mixture was extracted twice with dichloromethane (5 mL eachtime). The combined organic layers were dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was dissolved in methanol (0.5 mL),and potassium carbonate (1 mg, 7 μmol) was added at ambient temperature.The resulting mixture was stirred overnight and then concentrated invacuo. The residue was purified by silica gel column chromatographyusing ethyl acetate, DCM/methanol (9/1), and DCM/methanol/NH₄OH(9/1/0.1) as eluent to give 1.6 mg compound 15. The structure wasconfirmed by comparison of the ¹H NMR spectrum with the reportedspectrum. ¹H NMR (400 MHz, CD₃OD) δ ppm 0.97-1.07 (m, 1 H) 1.11 (d,J=6.3 Hz, 3 H) 1.30-1.62 (m, 6 H) 1.67-2.26 (m, 13 H) 2.27-2.42 (m, 3 H)2.42-2.51 (m, 2 H) 2.62-2.78 (m, 2 H) 2.83-2.96 (m, 3 H) 3.04 (dd,J=12.7, 3.3 Hz, 1 H) 3.37 (d, J=3.1 Hz, 1 H) 3.43 (s, 3 H) 3.74 (d,J=11.7 Hz, 1 H) 3.82-4.02 (m, 5 H) 4.08-4.14 (m, 2 H) 4.18 (dd, J=4.7,6.6 Hz, 1 H) 4.26-4.35 (m, 2 H) 4.48 (d, J=10.9 Hz, 1 H) 4.62 (t, J=4.3Hz, 1 H) 4.71 (t, J=4.3 Hz, 1 H) 4.82-4.84 (m, 1 H) 4.86-4.87 (m, 1 H)5.02 (br. s, 1 H) 5.14 (d, J=1.6 Hz, 1 H)

Example 4 Preparation of a Compound of Formula (ID) Through C.3-C.4Macrocyclization

(R)-1-((3aR,4S,6S,7S,7aR)-7-acetoxy-6-allyltetrahydro-3aH-spiro[[1,3]dioxolo[4,5-c]pyran-2,1′-cyclohexan]-4-yl)ethane-1,2-diyldiacetate

To a solution of(3aR,4S,6S,7R,7aR)-4-((R)-1,2-diacetoxyethyl)tetrahydro-3aH-spiro[[1,3]dioxolo[4,5-c]pyran-2,1′-cyclohexane]-6,7-diyldiacetate(10 g, 21.812 mmol) in acetonitrile (70.0 mL) was addedallyltrimethylsilane (10.40 mL, 65.44 mmol). The resulting solution wascooled to 0° C., and BF₃.OEt₂ (5.53 mL, 43.6 mmol) was added, while theinternal temperature was maintained below 10° C. After being stirred for6 h at a temperature between 0 and 10° C., the reaction mixture wastreated with saturated aqueous NaHCO₃ (8%) (100 mL). The resultingmixture was extracted with toluene (200 mL). The combined organic layerswere washed twice with water (200 mL) and concentrated in vacuo to give11 g of the target product as a white solid.

¹ H NMR (400 MHz, CDCl₃) δ ppm 1.23-1.85 (m, 10 H) 2.07 (s, 3 H) 2.10(s, 3 H) 2.14 (s, 3 H) 2.21-2.33 (m, 2 H) 3.74 (dd, J=7.6, 1.8 Hz, 1 H)4.11 (ddd, J=9.7, 6.6, 5.1 Hz, 1 H) 4.25 (dd, J=12.6, 4.4 Hz, 1 H) 4.32(dd, J=7.9, 1.8 Hz, 1 H) 4.46 (dd, J=12.6, 2.6 Hz, 1 H) 4.59 (dd, J=7.9,2.6 Hz, 1 H) 4.92 (dd, J=9.7, 2.6 Hz, 1 H) 5.07 (t, J=1.2 Hz, 1 H)5.09-5.16 (m, 1 H) 5.22 (ddd, J=7.5, 4.8, 2.6 Hz, 1 H) 5.69-5.90 (m, 1H).

(R)-1-((3aR,4S,6S,7S,7aS)-6-allyl-7-hydroxytetrahydro-3aH-spiro[[1,3]dioxolo[4,5-c]pyran-2,1′-cyclohexan]-4-yl)ethane-1,2-diol

To a solution of(R)-1-((3aR,4S,6S,7S,7aR)-7-acetoxy-6-allyltetrahydro-3aH-spiro[[1,3]dioxolo[4,5-c]pyran-2,1′-cyclohexan]-4-yl)ethane-1,2-diyldiacetate(11.0 g, 21.7 mmol) in methanol (12 mL) and MTBE (57 mL) was addedsodium methoxide solution in MeOH (25 wt %, 7.45 mL, 32.6 mmol) atambient temperature. After 2.5 h, the reaction mixture was cooled to10-15° C. Acetic acid (2.0 mL, 35 mmol) was added while keeping theinternal temperature below 20° C. The resulting mixture was concentratedin vacuo. Saturated aqueous NaHCO₃ (8%) (38.3 mL) was added and theresulting mixture was extracted four times with EtOAc (191 mL). Thecombined organic layers were washed with 30% aqueous NaCl (19 mL) anddried over MgSO₄. Filtration, concentration in vacuo, and purificationby silica gel column chromatography using a 50-100% gradient of ethylacetate in n-heptane as eluent provided 6.75 g of the target product asa yellow solid.

¹ H NMR (400 MHz, CDCl₃) δ ppm 1.33-1.80 (m, 10 H) 2.29-2.39 (m, 1 H)2.47-2.56 (m, 1 H) 3.58-3.67 (m, 2 H) 3.73 (dd, J=11.7, 4.1 Hz, 1 H)3.78 (dd, J=12.0, 3.8 Hz, 1 H) 3.83-3.95 (m, 2 H) 4.43 (dd, J=8.1, 1.6Hz, 1 H) 4.54 (dd, J=7.9, 3.5 Hz, 1 H) 5.03-5.30 (m, 2 H) 5.78-5.99 (m,1 H).

(R)-1-((3aR,4S,6S,7S,7aS)-6-allyl-7-hydroxytetrahydro-3aH-spiro[[1,3]dioxolo[4,5-c]pyran-2,1′-cyclohexan]-4-yl)ethane-1,2-diol(1.0 g, 3.18 mmol) was dissolved in acetone (5.0 mL, 68.1 mmol) atambient temperature. 2,2-Dimethoxypropane (1.369 mL, 11.13 mmol) andp-toluenesulfonic acid monohydrate (0.061 g, 0.318 mmol) were added, andthe resulting mixture was stirred for 30 min. Saturated aqueous NaHCO₃(10 mL) were added, and the resulting mixture was extracted three timeswith EtOAc (12 mL each time). The combined organic layers were washedwith brine (5 mL) and dried over MgSO₄. Filtration followed byconcentration in vacuo gave 1.09 g of the target product as a whitesolid.

(3aR,4S,6S,7S,7aR)-6-allyl-4-((R)-1,2-dihydroxyethyl)tetrahydro-3aH-spiro[[1,3]dioxolo[4,5-c]pyran-2,1′-cyclohexan]-7-ylbenzoate

To a solution of(3aR,4S,6S,7S,7aS)-6-allyl-4-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)tetrahydro-3aH-spiro[[1,3]dioxolo[4,5-c]pyran-2,1′-cyclohexan]-7-o(1.09 g, 3.075 mmol) in pyridine (5.45 mL) at ambient temperature wereadded benzoyl chloride (0.714 mL, 6.151 mmol) and4-dimethylaminopyridine (0.019 g, 0.154 mmol). After completeconsumption of the starting material, saturated aqueous NH₄Cl (27 wt %)(15 mL), MTBE (40 mL), and water (5.0 mL) were added. The layers wereseparated, and the organic layer was washed sequentially with 1M aqueoushydrochloric acid (10 mL, 10.00 mmol), saturated aqueous NaHCO₃ (8%)(5.0 mL), and 30% aqueous NaCl (5.0 mL). The resulting organic layer wasdried over MgSO₄, filtered and concentrated in vacuo. The residue (1.1g) was dissolved in acetic acid (16 mL) and water (4 mL). The resultingmixture was stirred at ambient temperature overnight and then at atemperature between 35 and 40° C. for 24 h. The mixture was thenconcentrated in vacuo and azeotroped twice with toluene. The residue waspurified by silica gel plug purification to give 1.1 g of the targetproduct as a pale yellow solid

(3aS,4R,6S,7S,7aR)-6-allyl-4-formyltetrahydro-3aH-spiro[[1,3]dioxolo[4,5-c]pyran-2,1-cyclohexan]-7-ylbenzoate

(3aR,4S,6S,7S,7aR)-6-allyl-4-((R)-1,2-dihydroxyethyl)tetrahydro-3aH-spiro[[1,3]dioxolo[4,5-c]pyran-2,1′-cyclohexan]-7-ylbenzoate (1.1 g, 2.629 mmol) was dissolved in ethyl acetate (11.00 mL)and water (11.00 mL) and cooled to 0° C. Sodium periodate (0.843 g,3.943 mmol) was added, and the resulting mixture was stirred for 2.5 hat ambient temperature. Additional sodium periodate (0.2 g) was thenadded. After additional stirring for 2.5 h, the layers were separated.The aqueous layer was extracted twice with EtOAc (11.00 mL), and thecombined organic layers were washed with 30% aqueous NaCl (5.50 mL) anddried over MgSO₄. Filtration followed by concentration in vacuo provided0.98 g of as a foam solid.

(3aR,4S,6S,7S,7aR)-6-allyl-4-((S,E)-1-hydroxy-3-(trimethylsilyl)allyl)tetrahydro-3aH-spiro[[1,3]dioxolo[4,5-c]pyran-2,1-cyclohexan]-7-ylbenzoate

To a solution of(3aS,4R,6S,7S,7aR)-6-allyl-4-formyltetrahydro-3aH-spiro[[1,3]dioxolo[4,5-c]pyran-2,1′-cyclohexan]-7-ylbenzoate (0.98 g) in acetonitrile (7 mL) was added(2-bromovinyl)trimethylsilane (1.941 mL, 12.68 mmol). The resultingsolution was degassed for 0.5 h. To another reactor were addedchromium(II) chloride (3.12 g, 25.36 mmol), nickel(II) chloride (0.033g, 0.254 mmol), DMSO (6.86 mL), and MeCN (6.86 mL), and the resultingmixture was cooled to 0-5° C. The aldehyde and vinyl bromide solutionwas added to the chromium and nickel mixture. The reaction mixture wasstirred overnight at a temperature between 5 and 15° C. and then treatedwith methanol (20.42 mL), water (20.58 mL), and MTBE (24.50 mL). Thelayers were separated, and the aqueous layer was extracted twice withMTBE (34.3 mL). The combined organic layers were washed twice with 30%aqueous NaCl (19.60 mL) and dried over MgSO₄. Filtration followed byconcentration in vacuo provided 0.521 g of the target product as whitefoam solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 0.07 (s, 9 H) 1.21-1.87 (m, 10 H)2.24-2.33 (m, 1 H) 2.34-2.43 (m, 1 H) 2.59-2.68 (m, 1 H) 3.49 (dd,J=6.6, 2.0 Hz, 1 H) 4.28-4.37 (m, 2 H) 4.54 (dd, J=8.0, 1.8 Hz, 1 H)4.72 (dd, J=7.8, 2.7 Hz, 1 H) 5.02-5.09 (m, 2 H) 5.13 (dd, J=9.8, 2.7Hz, 1 H) 5.77-5.93 (m, 1 H) 6.07 (dd, J=18.7, 1.6 Hz, 1 H) 6.23 (dd,J=19.1, 4.3 Hz, 1 H) 7.43-7.48 (m, 2 H) 7.57 (d, J=7.4 Hz, 1 H) 8.07(dd, J=8.4, 1.4 Hz, 2 H)

(2S,3R,4R,5S,6S)-2-allyl-4,5-dihydroxy-6-((S,E)-1-hydroxy-3-(trimethylsilyl)allyl)tetrahydro-2H-pyran-3-ylbenzoate

To(3aR,4S,6S,7S,7aR)-6-allyl-4-((S,E)-1-hydroxy-3-(trimethylsilyl)allyl)tetrahydro-3aH-spiro[[1,3]dioxolo[4,5-c]pyran-2,1′-cyclohexan]-7-ylbenzoate(0.521 g, 1.071 mmol) were added acetic acid (7.8 mL) and water (7.8mL). The reaction mixture was heated to 90-97° C. for 100 min andconcentrated in vacuo. The residue was azeotroped with toluene andpurified by silica gel plug to give 0.33 g of the target product as awhite foam solid.

(2S,3S,4S,5R,6S)-2-allyl-4,5-bis((tert-butyldimethylsilyl)oxy)-6-((S,E)-1-((tert-butyldimethylsilyl)oxy)-3-(trimethylsilyl)allyl)tetrahydro-2H-pyran-3-ylbenzoate

(2S,3R,4R,5S,6S)-2-allyl-4,5-dihydroxy-6-((S,E)-1-hydroxy-3-(trimethylsilyl)allyl)tetrahydro-2H-pyran-3-ylbenzoate (0.33 g) was dissolved in MTBE (4.95 mL) and cooled to 0° C.2,6-Dimethylpyridine (0.95 mL, 8.1 mmol) and tert-butyldimethylsilyltrifluoromethanesulfonate (0.84 mL, 3.7 mmol) were added. The resultingmixture was stirred at ambient temperature overnight. Saturated aqueousNH₄Cl (27 wt %) (4.95 mL), MTBE (9.90 mL), and water (3.30 mL) wereadded. The organic layer was separated and dried over MgSO₄. Filtration,concentration, and purification by silica gel column chromatographyusing a 0-10% gradient of ethyl acetate in n-heptane as eluent afforded0.619 g of the target product as an oil.

(2S,3S,4S,5R,6S)-2-allyl-4,5-bis((tert-butyldimethylsilyl)oxy)-6-((S,E)-1-((tert-butyldimethylsilyl)oxy)-3-iodoallyl)tetrahydro-2H-pyran-3-ylbenzoate

(2S,3S,4S,5R,6S)-2-allyl-4,5-bis((tert-butyldimethylsilyl)oxy)-6-((S,E)-1-((tert-butyldimethylsilyl)oxy)-3-(trimethylsilyl)allyl)tetrahydro-2H-pyran-3-ylbenzoate (0.510 g, 0.681 mmol) was dissolved in toluene (2.295 mL) andMeCN (4.59 mL) at ambient temperature. To the solution were addedtert-butyldimethylsilyl chloride (7.69 mg, 0.051 mmol) and NIS (0.919 g,4.08 mmol). The reaction mixture was stirred at 28-31° C. for 20 h andcooled to ambient temperature. Toluene (24.29 mL), sodium thiosulfate(1.076 g, 6.806 mmol) and saturated aqueous NaHCO₃ (8%) (5.10 mL) wereadded, and the resulting mixture was stirred over 2 h at ambienttemperature. The layers were separated, and the organic layer was washedtwice with 30% aqueous NaCl (7.29 mL) and dried over MgSO₄. Filtrationfollowed by concentration and purification by silica gel columnchromatography using a 0-10% gradient of ethyl acetate in n-heptane aseluent provided 467 mg of the target product as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ ppm −0.04-0.27 (m, 18 H) 0.89 (br. s., 9 H)0.90 (br. s., 9 H) 0.96 (s, 9 H) 2.22-2.53 (m, 2 H) 3.24-3.69 (m, 1 H)3.76-4.50 (m, 4 H) 4.95-5.35 (m, 3 H) 5.71-5.90 (m, 1 H) 6.36 (d, J=14.9Hz, 1 H) 6.50-6.73 (m, 1 H) 7.33-7.46 (m, 1 H) 7.48-7.60 (m, 2 H)7.96-8.15 (m, 2 H).

(S)-5-(((2R,3R,4S,5S)-3-methoxy-5-(((2R,4R,6S)-4-methyl-3-methylene-6-(2-((2S,5S)-3-methylene-5-(3-((triethylsilyl)oxy)propyl)tetrahydrofuran-2-yl)ethyl)tetrahydro-2H-pyran-2-yl)methyl)-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane

3-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)propan-1-ol(1.00 g, 1.175 mmol) was dissolved in dichloromethane (7.00 mL) atambient temperature. Imidazole (0.240 g, 3.52 mmol) andchlorotriethylsilane (0.300 mL, 1.76 mmol) were added, and the resultingmixture was stirred at ambient temperature for 1 h., at which time asaturated aqueous NH₄Cl (27 wt %) (12.00 mL, 64.205 mmol) was added, andthe resulting mixture was extracted with MTBE (15.00 mL, 125.924 mmol).The combined organic layers were washed with 30% aqueous NaCl (10.00 mL,52.578 mmol) and dried over MgSO₄. Concentration and azeotroping withtoluene provided 1.177 g of the target product as an oil.

Methyl(R)-2-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(2-((2S,5S)-3-methylene-5-(3-((triethylsilyl)oxy)propyl)tetrahydrofuran-2-yl)ethyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)-2-(phenylsulfonyl)acetate

(S)-5-(((2R,3R,4S,5S)-3-methoxy-5-(((2R,4R,6S)-4-methyl-3-methylene-6-(2-((2S,5S)-3-methylene-5-(3-((triethylsilyl)oxy)propyl)tetrahydrofuran-2-yl)ethyl)tetrahydro-2H-pyran-2-yl)methyl)-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane(1.177 g, 1.17 mmol) was dissolved in THF (11.3 mL) and cooled to 0° C.n-BuLi (1.6 M, 0.95 mL, 1.5 mmol) was added. The resulting solution wasstirred for 20 min at 0° C. and cooled to −78° C. Methyl chloroformate(0.14 mL, 1.8 mmol) was added, and the resulting solution was stirredfor 1.5 h with warming to −40° C. Saturated aqueous NH₄Cl (27 wt %) (10mL), water (5 mL) and MTBE (11 mL) were added, and the resulting mixturewas warmed to ambient temperature. The layers were separated, and theorganic layer was washed with saturated aqueous NaCl (4 mL) and driedover MgSO₄. Filtration followed by concentration in vacuo provided 1.267g of the target product as colorless oil.

methyl2-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(2-((2S,5S)-3-methylene-5-(3-((triethylsilyl)oxy)propyl)tetrahydrofuran-2-yl)ethyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)acetate

(S)-methyl2-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(2-((2S,5S)-3-methylene-5-(3-((triethylsilyloxy)propyl)tetrahydrofuran-2-yl)ethyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)-2-(phenylsulfonyl)acetate(1.267 g, 1.176 mmol) was dissolved in methanol (36.1 mL) at ambienttemperature. Magnesium (0.286 g, 11.8 mmol) was added, and the resultingmixture was stirred at ambient temperature. Additional magnesium (0.56g) and methanol (32 mL) were added over 20 h. Once the starting materialwas consumed, the reaction mixture was cooled below 10° C. and treatedwith sodium phosphate, monobasic (4.66 g, 38.8 mmol). The resultingmixture was concentrated in vacuo. To the residue were added MTBE (36.1mL), saturated aqueous NH₄Cl (27 wt %) (18.0 mL), and water (12.0 mL).The resulting mixture was stirred at ambient temperature and filteredthrough a Celite® pad. The layers were separated, and the aqueous layerwas extracted with MTBE (24.0 mL). The combined organic layers werewashed with 30% aqueous NaCl (12.0 mL), dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was dissolved in dichloromethane(12.0 mL) at ambient temperature and treated with imidazole (0.400 g,5.88 mmol) and chlorotriethylsilane (0.59 mL, 3.53 mmol). After 2 h atambient temperature, the reaction was quenched with saturated aqueousNH₄Cl solution (10 mL). The resulting mixture was extracted with MTBE(30 mL). The organic layer was washed with 30% aqueous NaCl (10 mL),dried over MgSO₄, and concentrated in vacuo. The residue was purified bysilica gel column chromatography using a 5-20% gradient of ethyl acetatein n-heptane as eluent to give 0.42 g of the target product as colorlessoil.

¹H NMR (400 MHz, CDCl₃) δ ppm 0.03 (s, 3 H) 0.04 (s, 3 H) 0.06 (s, 3 H)0.07 (s, 3 H) 0.55-0.62 (m, 6 H) 0.87-0.88 (m, 9 H) 0.88 (s, 9 H)0.92-0.97 (m, 9 H) 1.07 (d, J=6.6 Hz, 3 H) 1.43-1.70 (m, 8 H) 1.79 (s, 2H) 1.92-2.02 (m, 2 H) 2.09-2.19 (m, 1 H) 2.20-2.45 (m, 6 H) 2.59-2.69(m, 1 H) 3.29 (s, 3 H) 3.41 (d, J=3.9 Hz, 1 H) 3.46-3.65 (m, 5 H)3.67-3.73 (m, 1 H) 3.69 (s, 3 H) 3.74-3.81 (m, 2 H) 3.83-3.91 (m, 1 H)3.95-4.06 (m, 1 H) 4.34-4.43 (m, 1 H) 4.79 (d, J=1.6 Hz, 1 H) 4.82 (d,J=2.0 Hz, 1 H) 4.87 (s, 1 H) 4.96 (d, J=2.0 Hz, 1 H).

methyl2-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(2-((2S,5S)-3-methylene-5-(3-oxopropyl)tetrahydrofuran-2-yl)ethyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)acetate

A solution of oxalyl chloride (0.2 M, 0.10 mL, 0.20 mmol) indichloromethane was diluted with dichloromethane (1.0 mL) and cooled to−78° C. A solution of DMSO (0.030 mL, 0.419 mmol) in dichloromethane(0.300 mL, 4.66 mmol) followed by a solution of methyl2-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(2-((2S,5S)-3-methylene-5-(3-((triethylsilyl)oxy)propyl)tetrahydrofuran-2-yl)ethyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)acetate(0.10 g, 0.113 mmol) in dichloromethane (0.500 mL) was added. Theresulting solution was stirred for 30 min at −50° C., cooled to −78° C.and treated with triethylamine (0.095 mL, 0.679 mmol). The mixture waswarmed to ambient temperature over 1 h, diluted with MTBE (15 mL), andwashed with saturated aqueous NH₄Cl solution (5 mL) and 30% aqueous NaCl(3 mL). The organic layer was dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was filtered through a silica gelplug with MTBE. Concentration of the filtrate in vacuo provided 89 mg ofthe target product as an oil.

¹H NMR (400 MHz, CDCl₃) δ ppm 0.04 (s, 3 H) 0.04 (s, 3 H) 0.06 (s, 3 H)0.07 (s, 3 H) 0.88 (s, 9 H) 0.89 (s, 9 H) 1.08 (d, J=6.3 Hz, 3 H)1.42-1.69 (m, 5 H) 1.74-1.85 (m, 4 H) 1.93-2.03 (m, 2 H) 2.10-2.19 (m, 1H) 2.22-2.32 (m, 3 H) 2.34-2.46 (m, 2 H) 2.47-2.62 (m, 2 H) 2.63-2.73(m, 1 H) 3.29 (s, 3 H) 3.42 (d, J=3.5 Hz, 1 H) 3.50 (d, J=5.1 Hz, 2 H)3.56 (d, J=5.9 Hz, 1 H) 3.67-3.73 (m, 1 H) 3.70 (s, 3 H) 3.78 (d, J=5.5Hz, 2 H) 3.84-3.91 (m, 1 H) 4.04 (quin, J=6.4 Hz, 1 H) 4.34 (d, J=6.6Hz, 1 H) 4.79-4.81 (m, 1 H) 4.84 (d, J=2.3 Hz, 1 H) 4.88 (s, 1 H) 4.98(d, J=2.3 Hz, 1 H) 9.79 (t, J=1.4 Hz, 1 H)

(2S,3S,4S,5R,6S)-2-allyl-6-((1S,E)-6-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-(2-methoxy-2-oxoethyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)-1-((tert-butyldimethylsilyl)oxy)-4-hydroxyhex-2-en-1-yl)-4,5-bis((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-3-ylbenzoate

(S)-N-(2-(4-isopropyl-4,5-dihydrooxazol-2-yl)-6-methylphenyl)methanesulfonamide(688 mg, 2.32 mmol) was dissolved in acetonitrile (4 mL) and purged withnitrogen for 30 min. Chromous chloride (285 mg, 2.32 mmol) andtriethylamine (320 μL, 2.32 mmol) were added, and the resulting darkgreen mixture was stirred at 35° C. for 1 h. In another reactor, methyl2-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(2-((2S,5S)-3-methylene-5-(3-oxopropyl)tetrahydrofuran-2-yl)ethyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)acetate(89 mg, 0.116 mmol) and(2S,3S,4S,5R,6S)-2-allyl-4,5-bis((tert-butyldimethylsilyl)oxy)-6-((S,E)-1-((tert-butyldimethylsilyl)oxy)-3-iodoallyl)tetrahydro-2H-pyran-3-ylbenzoate (107 mg, 0.133 mmol) were dissolved in THF (870 μL) andacetonitrile (680 μL) and purged with nitrogen for 10 min.

Nickel(II) chloride complex with 2,9-dimethyl-1,10-phenanthroline (7.84mg, 0.023 mmol) followed by the sulfonamide complex solution preparedabove was added. The resulting mixture was stirred vigorously for 5 h at15-23° C. and diluted with n-heptane (6.5 mL). The resulting mixture wasfiltered through a Celite® pad, which was then rinsed with n-heptane (10mL) and acetonitrile (10 mL). The layers were separated, and the bottomacetonitrile layer was extracted twice with n-heptane (7 mL each). Thecombined n-heptane layers were washed twice with acetonitrile (5 mLeach) and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography using a 10-33% gradient of ethyl acetate inn-heptane as eluent to give 99 mg of the target product as white foamsolid.

(2S,3S,4S,5R,6S)-2-allyl-6-((S,E)-6-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-(2-methoxy-2-oxoethyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)-1-((tert-butyldimethylsilyl)oxy)-4-oxohex-2-en-1-yl)-4,5-bis((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-3-ylbenzoate

To a solution of(2S,3S,4S,5R,6S)-2-allyl-6-((1S,E)-6-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-(2-methoxy-2-oxoethyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)-1-((tert-butyldimethylsilyl)oxy)-4-hydroxyhex-2-en-1-yl)-4,5-bis((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-3-ylbenzoate (0.284 g, 0.197 mmol) in dichloromethane (5.7 mL) at ambienttemperature were added sodium bicarbonate (83 mg, 0.98 mmol) andDess-Martin periodinane (250 mg, 0.59 mmol). After being stirred over 2h at ambient temperature, the reaction mixture was diluted with MTBE(8.5 mL). Water (2.8 mL), sodium thiosulfate (0.155 mg, 0.983 mmol), andsaturated aqueous NaHCO₃ (8%) (2.84 mL) were added, and the resultingmixture was stirred for 30 min. The layers were separated, and theorganic layer was washed twice with 30% aqueous NaCl (1.4 mL each time)and dried over MgSO₄. Filtration and concentration in vacuo provided 270mg of the target product as white foam.

¹H NMR (400 MHz, CDCl₃) δ ppm −0.13-0.23 (m, 30 H) 0.87 (s, 9 H) 0.88(br. s, 18 H) 0.90-0.91 (m, 9 H) 0.96 (s, 9 H) 1.07 (d, J=6.3 Hz, 3 H)1.41-1.70 (m, 6 H) 1.72-1.86 (m, 4 H) 1.93-2.03 (m, 2 H) 2.09-2.19 (m, 1H) 2.20-2.56 (m, 7 H) 2.57-2.80 (m, 3 H) 3.29 (s, 3 H) 3.41 (d, J=3.5Hz, 2 H) 3.43-3.55 (m, 4 H) 3.56 (m, J=5.5 Hz, 1 H) 3.65-3.73 (m, 1 H)3.69 (s, 3 H) 3.74-3.82 (m, 2 H) 3.84-3.90 (m, 1 H) 3.92-4.15 (m, 4 H)4.30-4.41 (m, 1 H) 4.59-4.70 (m, 1 H) 4.79 (d, J=1.2 Hz, 1 H) 4.81-4.85(m, 1 H) 4.87 (s, 1 H) 4.95-5.00 (m, 1 H) 5.05-5.29 (m, 2 H) 5.62-5.83(m, 1 H) 6.27 (d, J=15.2 Hz, 1 H) 6.65-6.85 (m, 1 H) 7.34-7.48 (m, 2 H)7.50-7.60 (m, 1 H) 7.92-8.14 (m, 2 H)

(2S,3aR,4aR,5R,6S,7S,8aR,8bS)-7-allyl-2-(2-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-dihydroxypropyl)-4-methoxy-3-(2-methoxy-2-oxoethyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)ethyl)octahydro-2H-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyran-6-ylbenzoate

(2S,3S,4S,5R,6S)-2-allyl-6-((S,E)-6-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tertbutyldimethylsilyl)oxy)propyl)-4-methoxy-3-(2-methoxy-2-oxoethyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)-1-((tert-butyldimethylsilyl)oxy)-4-oxohex-2-en-1-yl)-4,5-bis((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-3-ylbenzoate (0.270 g, 0.187 mmol) was dissolved in N,N-dimethylacetamide(4.3 mL), and THF (10.8 mL) at ambient temperature. A mixture oftetrabutylammonium fluoride (1.0 M, 1.9 mL, 1.9 mmol) and imidazolehydrochloride (0.098 g, 0.936 mmol) was added, and the resultingsolution was stirred at ambient temperature for 20 h. Water (5.4 mL) andtoluene (11 mL) were added and the layers were separated. The aqueouslayer was extracted twice with a mixture of toluene (11 mL) and THF (11mL). The combined organic layers were washed with 30% aqueous NaCl (5.4mL), dried over MgSO₄, filtered, and concentrated in vacuo. The residuewas azeotroped with a mixture of acetonitrile (3.2 mL) and water (1.1mL) three times to give 0.26 g of brown oil. The crude product wasdissolved in dichloromethane (5.0 mL) and treated with DBU (0.050 mL,0.332 mmol) for 1 h at ambient temperature. Pyridiniump-toluenesulfonate (496 mg, 1.98 mmol) was added, and the resultingmixture was stirred for 3 h at ambient temperature. The reaction mixturewas purified by silica-gel column chromatography using a 0-100% gradientof acetonitrile in ethyl acetate as eluent to afford 44 mg of the targetproduct.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.08 (d, J=6.6 Hz, 3 H) 1.43-2.49 (m, 23H) 2.68 (ddd, J=15.7, 6.5, 1.6 Hz, 1 H) 3.32 (s, 3 H) 3.46-3.57 (m, 3 H)3.61-3.66 (m, 1 H) 3.69 (s, 3 H) 3.76 (dd, J=9.0, 3.9 Hz, 1 H) 3.83 (dt,J=7.7, 5.3 Hz, 1 H) 3.90-4.01 (m, 2 H) 4.03 (d, J=7.0 Hz, 1 H) 4.21 (dd,J=6.6, 4.3 Hz, 1 H) 4.30 (dd, J=6.4, 4.5 Hz, 1 H) 4.35-4.40 (m, 1 H)4.64 (dd, J=4.1, 2.1 Hz, 1 H) 4.66-4.69 (m, 1 H) 4.70-4.80 (m, 3 H) 4.81(d, J=1.6 Hz, 1 H) 4.85 (d, J=1.6 Hz, 1 H) 4.86 (s, 1 H) 4.97 (d, J=2.0Hz, 1 H) 5.00-5.04 (m, 1 H) 5.06 (d, J=1.6 Hz, 1 H) 5.80-5.99 (m, 1 H)7.41-7.46 (m, 2 H) 7.54-7.59 (m, 1 H) 8.04 (dd, J=8.4, 1.4 Hz, 2 H).

methyl2-((2S,3S,4R,5R)-2-(((2R,4R,6S)-6-(2-((2S,5S)-5-(2-((3aR,4aR,5R,6S,7S,8aR,8bS)-7-allyl-6-((triethylsilyl)oxy)octahydro-2H-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyran-2-yl)ethyl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-5-((S)-2,3-bis((triethylsilyl)oxy)propyl)-4-methoxytetrahydrofuran-3-yl)acetate

(3aR,4aR,5R,6S,7S,8aR,8bS)-7-allyl-2-(2-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-dihydroxypropyl)-4-methoxy-3-(2-methoxy-2-oxoethyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)ethyl)octahydro-2H-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyran-6-ylbenzoate (48.7 mg, 0.057 mmol) was dissolved in THF (1.5 mL) and cooledto 0° C. A solution of sodium methoxide in methanol (25 wt %, 17 μL,0.074 mmol) was added, and the resulting solution was stirred at ambienttemperature for 1 h. Acetic acid (6.54 μL, 0.114 mmol) was added, andsolvents were removed with a stream of nitrogen. The residue wasazeotroped with toluene and dissolved in DMF (1.5 mL) at ambienttemperature. To the resulting solution were added imidazole (58.4 mg,0.857 mmol), chlorotriethylsilane (0.096 mL, 0.572 mmol), and4-dimethylaminopyridine (7.0 mg, 0.057 mmol). The resulting mixture wasstirred at ambient temperature for 2 days and then treated withsaturated aqueous NaHCO₃ (8%) (3.0 mL). The resulting mixture wasextracted twice with MTBE (12 mL). The combined organic layers werewashed with 30% aqueous NaCl (4.0 mL) and dried over MgSO₄. Filtrationfollowed by concentration and purification by silica gel columnchromatography using a 10-33% gradient of ethyl acetate in n-heptane aseluent provided 110 mg of the target product.

2-((2S,3S,4R,5R)-2-(((2R,4R,6S)-6-(2-((2S,5S)-5-(2-((2S,3aR,4aR,5R,6S,7S,8aR,8bS)-7-allyl-6-((triethylsilyl)oxy)octahydro-2H-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyran-2-yl)ethyl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-5-((S)-2,3-bis((triethylsilyl)oxy)propyl)-4-methoxytetrahydrofuran-3-yl)ethan-1-ol

methyl2-((2S,3S,4R,5R)-2-(((2R,4R,6S)-6-(2-((2S,5S)-5-(2-((3aR,4aR,5R,6S,7S,8aR,8bS)-7-allyl-6-((triethylsilyl)oxy)octahydro-2H-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyran-2-yl)ethyl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-5-((S)-2,3-bis((triethylsilyl)oxy)propyl)-4-methoxytetrahydrofuran-3-yl)acetate(110 mg) was dissolved in THF (3.0 mL) and cooled to 0° C. A solution oflithium aluminum hydride in THF (1.0 M, 0.11 mL, 0.11 mmol) was added,and the resulting solution was stirred for 30 min. Saturated aqueousNH₄Cl (27 wt %) (3.0 mL) and water (1 mL) were added, and the resultingmixture was extracted twice with MTBE (6 mL each time). The combinedorganic layers were washed with 30% aqueous NaCl (4.0 mL) and dried overMgSO₄. Filtration followed by concentration and purification by silicagel column chromatography using a 25-50% gradient of ethyl acetate inn-heptane as eluent provided 26.6 mg of the target product.

¹H NMR (400 MHz, CDCl₃) δ ppm 0.56-0.65 (m, 18 H) 0.91-0.99 (m, 27 H)1.07 (d, J=6.2 Hz, 3 H) 1.46-1.83 (m, 12 H) 1.89-2.17 (m, 8 H) 2.20-2.31(m, 2 H) 2.51-2.59 (m, 1 H) 2.60-2.69 (m, 1 H) 3.22 (dd, J=9.4, 2.3 Hz,1 H) 3.30 (s, 3 H) 3.45 (dd, J=4.3, 3.1 Hz, 1 H) 3.50-3.62 (m, 3 H)3.68-3.78 (m, 3 H) 3.78-3.84 (m, 1 H) 3.84-3.90 (m, 1 H) 3.90-3.96 (m, 1H) 3.97-4.05 (m, 2 H) 4.18 (dd, J=6.6, 4.7 Hz, 1 H) 4.29 (dd, J=4.1, 2.1Hz, 1 H) 4.30-4.36 (m, 1 H) 4.37-4.43 (m, 1 H) 4.58 (t, J=4.5 Hz, 1 H)4.66 (t, J=4.7 Hz, 1 H) 4.79-4.80 (m, 1 H) 4.83 (d, J=2.0 Hz, 1 H) 4.88(s, 1 H) 4.96 (d, J=2.0 Hz, 1 H) 5.07 (d, J=10.2 Hz, 1 H) 5.14 (d, J=1.2Hz, 1 H) 5.91 (dddd, J=17.3, 10.1, 7.7, 5.9 Hz, 1 H)

2-((2S,3S,4R,5R)-2-(((2R,4R,6S)-6-(2-((2S,5S)-5-(2-((3aR,4aR,5R,6S,7S,8aR,8bS)-7-allyl-6-((triethylsilyl)oxy)octahydro-2H-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyran-2-yl)ethyl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-5-((S)-2,3-bis((triethylsilyl)oxy)propyl)-4-methoxytetrahydrofuran-3-yl)acetaldehyde

To a solution of2-((2S,3S,4R,5R)-2-(((2R,4R,6S)-6-(2-((2S,5S)-5-(2-((3aR,4aR,5R,6S,7S,8aR,8bS)-7-allyl-6-((triethylsilyl)oxy)octahydro-2H-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyran-2-yl)ethyl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-5-((S)-2,3-bis((triethylsilyl)oxy)propyl)-4-methoxytetrahydrofuran-3-yl)ethanol(13.3 mg, 0.013 mmol) in dichloromethane (1.0 mL) at ambient temperaturewere added sodium bicarbonate (10.5 mg, 0.125 mmol) and Dess-Martinperiodinane (26.5 mg, 0.063 mmol). After being stirred for 40 min, thereaction mixture was treated with MTBE (6.0 mL), water (3.0 mL) andsodium thiosulfate (15.82 mg, 0.10 mmol). After 10 min of being stirred,the layers were separated, and the organic layer was washed twice with30% aqueous NaCl (2.0 mL) and dried over MgSO₄. Concentration in vacuoprovided 12 mg of the target product.

1-((2S,3S,4R,5R)-2-(((2R,4R,6S)-6-(2-((2S,5S)-5-(2-((3aR,4aR,5R,6S,7S,8aR,8bS)-7-allyl-6-((triethylsilyl)oxy)octahydro-2H-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyran-2-yl)ethyl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-5-((S)-2,3-bis((triethylsilyl)oxy)propyl)-4-methoxytetrahydrofuran-3-yl)pent-4-en-2-ol

2-((2S,3S,4R,5R)-2-(((2R,4R,6S)-6-(2-((2S,5S)-5-(2-((3aR,4aR,5R,6S,7S,8aR,8bS)-7-allyl-6-((triethylsilyl)oxy)octahydro-2H-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyran-2-yl)ethyl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-5-((S)-2,3-bis((triethylsilyl)oxy)propyl)-4-methoxytetrahydrofuran-3-yl)acetaldehyde(12 mg, 0.011 mmol) was dissolved in THF (1.0 mL) and cooled to 0° C. Asolution of allylmagnesium chloride in THF (2.0 M, 0.017 mL, 0.034 mmol)was added. The resulting solution was stirred for 20 min and thentreated with saturated aqueous NH₄Cl (27 wt %) (3.0 mL). The resultingmixture was extracted with MTBE (10 mL). The organic layer was washedtwice with 30% aqueous NaCl (2.0 mL), dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was purified by silica gel columnchromatography using a 20-33% gradient of ethyl acetate in n-heptane aseluent provided 11.7 mg of the target product.

1-((2S,3S,4R,5R)-2-(((2R,4R,6S)-6-(2-((2S,5S)-5-(2-((3aR,4aR,5R,6S,7S,8aR,8bS)-7-allyl-6-((triethylsilyl)oxy)octahydro-2H-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyran-2-yl)ethyl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-5-((S)-2,3-bis((triethylsilyl)oxy)propyl)-4-methoxytetrahydrofuran-3-yl)pent-4-en-2-ol(11.7 mg, 10.60 μmol) was dissolved in toluene (10 mL) and heated to 50°C. Hoveyda-Grubbs 2nd Generation Catalyst (1.333 mg, 2.12 μmol) wasadded, and the resulting solution was stirred for 3 h at a temperaturebetween 68-73° C. The reaction mixture was cooled to ambient temperatureand purified by silica gel column chromatography using a 20-33% gradientof ethyl acetate in n-heptane as eluent to provide 7.7 mg of the targetproduct. ¹H NMR (400 MHz, CDCl₃) δ ppm 0.56-0.68 (m, 18 H) 0.85-1.02 (m,27 H) 1.08 (d, J=6.2 Hz, 3 H) 1.28-2.35 (m, 23 H) 2.39-2.84 (m, 3 H)3.17 (ddd, J=9.5, 5.6, 2.1 Hz, 1 H) 3.31 (s, 3 H) 3.41-3.64 (m, 4 H)3.65-4.07 (m, 6 H) 4.17 (d, J=6.6 Hz, 1 H) 4.28 (dd, J=4.1, 2.1 Hz, 1 H)4.31-4.41 (m, 3 H) 4.56-4.69 (m, 2 H) 4.79 (s, 1 H) 4.83 (br. s., 1 H)4.92 (s, 1 H) 4.96 (d, J=2.3 Hz, 1 H) 5.45-5.61 (m, 1 H) 5.62-5.76 (m, 1H)

The starting material (7.7 mg, 7.158 μmol) was dissolved indichloromethane (0.70 mL) and treated with sodium bicarbonate (6.01 mg,0.072 mmol) and Dess-Martin periodinane (12.14 mg, 0.029 mmol). Afterbeing stirred at ambient temperature for 1 h, the reaction mixture wasdiluted with MTBE (5.0 mL) and water (3.0 mL). Sodium thiosulfate (11.32mg, 0.072 mmol) was added and the resulting mixture was stirred at for20 min. The layers were separated and the organic layer was washed with30% aqueous NaCl (1.0 mL) and dried over MgSO₄. Filtration followed byconcentration and purification by silica gel column chromatography usingn-heptane/ethyl acetate (2/1) as eluent afforded 6.8 mg of the targetproduct as a film.

¹H NMR (400 MHz, CDCl₃) δ ppm 0.55-0.65 (m, 18 H) 0.91-1.02 (m, 27 H)1.08 (d, J=6.6 Hz, 3 H) 1.40-2.33 (m, 20 H) 2.49-2.67 (m, 4 H) 3.03 (dd,J=15.6, 7.8 Hz, 1 H) 3.08-3.14 (m, 1 H) 3.16 (dd, J=9.4, 2.0 Hz, 1 H)3.30 (d, J=3.1 Hz, 1 H) 3.35 (s, 3 H) 3.44-3.57 (m, 3 H) 3.73-3.87 (m, 3H) 3.87-3.94 (m, 1 H) 3.97-4.00 (m, 1 H) 4.18 (dd, J=6.6, 4.3 Hz, 1 H)4.29 (dd, J=4.1, 2.1 Hz, 1 H) 4.32-4.44 (m, 3 H) 4.59-4.66 (m, 2 H) 4.79(s, 1 H) 4.83 (s, 1 H) 4.91 (s, 1 H) 4.98 (s, 1 H) 5.57 (dt, J=15.2, 7.0Hz, 1 H) 5.69 (dt, J=14.8, 6.2 Hz, 1 H)

To a solution of compound 7 (3.4 mg, 3.167 μmol) in THF (0.5 mL) atambient temperature was added TBAF (1.0 M, 0.025 mL, 0.025 mmol). Theresulting solution was stirred for 25 h at ambient temperature and thenpurified by silica gel column chromatography using a 0-100% gradient ofacetonitrile in ethyl acetate as eluent to provide 1.6 mg of the targetproduct. The structure was confirmed by comparison of the ¹H NMRspectrum to that of an authentic sample.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.10 (d, J=6.6 Hz, 1 H) 1.19-1.83 (m, 8 H)1.92-2.36 (m, 12 H) 2.39-2.58 (m, 3 H) 2.72 (dd, J=16.0, 9.8 Hz, 1 H)2.82-2.92 (m, 2 H) 2.94-3.02 (m, 1 H) 3.29 (d, J=3.1 Hz, 1 H) 3.44 (s, 3H) 3.51-3.69 (m, 4 H) 3.86 (dt, J=9.0, 3.1 Hz, 1 H) 3.89-3.99 (m, 3 H)4.03 (dd, J=6.3, 4.3 Hz, 1 H) 4.08-4.16 (m, 1 H) 4.19 (dd, J=6.6, 4.7Hz, 1 H) 4.26-4.41 (m, 3 H) 4.61 (t, J=4.7 Hz, 1 H) 4.69 (t, J=4.3 Hz, 1H) 4.82 (d, J=1.6 Hz, 1 H) 4.89 (br. s., 1 H) 4.93 (br. s, 1 H) 5.07 (d,J=2.0 Hz, 1 H)

Example 5 Preparation of a Compound of Formula (ID) Through C.2-C.3Macrocyclization Methyl2-((2S,3S,4R,5R)-5-((S)-2,3-bis((triethylsilyl)oxy)propyl)-2-(((2R,4R,6S)-6-(2-((2S,5S)-5-(2-((2S,3aR,4aR,5R,6S,7S,8aR,8bS)-7-(3-hydroxypropyl)-6-((triethylsilyl)oxy)octahydro-2H-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyran-2-yl)ethyl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-4-methoxytetrahydrofuran-3-yl)acetate

To a solution of methyl2-((2S,3S,4R,5R)-2-(((2R,4R,6S)-6-(2-((2S,5S)-5-(2-((3aR,4aR,5R,6S,7S,8aR,8bS)-7-allyl-6-((triethylsilyl)oxy)octahydro-2H-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyran-2-yl)ethyl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-5-((S)-2,3-bis((triethylsilyl)oxy)propyl)-4-methoxytetrahydrofuran-3-yl)acetate(10 mg, 9.16 μmol) in THF (0.2 mL) was added the freshly preparedsolution of disiamylborane in THF (0.45 M, 0.041 mL, 0.018 mmol) at 0°C. The resulting solution was warmed to ambient temperature. After 1 h,2 h, and 4 h, additional diisoamylborane solution was added (each time40 μL). After being stirred for 2 h, the reaction mixture was dilutedwith MTBE (1.0 mL) and cooled down to 0° C. 3M Sodium hydroxide (0.10mL, 0.30 mmol) and 30% hydrogen peroxide (0.10 mL, 0.979 mmol) wereadded. The resulting mixture was stirred at ambient temperature for 2 hand treated with saturated aqueous NH₄Cl solution (2 m) and MTBE (2 mL).The layers were separated, and the aqueous layer was extracted with MTBE(3 mL). The combined organic layers were washed with saturated aqueousNaHSO₃ (1 mL) and 30% aqueous NaCl (1 mL) and dried over MgSO₄.Filtration followed by concentration in vacuo and purification by silicagel column chromatography using a 20-33% gradient of ethyl acetate inn-heptane as eluent provided 3.6 mg of the target product.

¹H NMR (400 MHz, CDCl₃) δ ppm 0.53-0.66 (m, 18 H) 0.91-0.99 (m, 27 H)1.08 (d, J=6.6 Hz, 3 H) 1.17-1.24 (m, 1 H) 1.36 (m, 2 H) 1.65-1.85 (m, 9H) 1.88-2.03 (m, 6 H) 2.14 (d, J=12.9 Hz, 2 H) 2.21-2.32 (m, 3 H) 2.35(m, 1 H) 2.40 (m, 1 H) 2.59-2.69 (m, 1 H) 3.19 (dd, J=9.6, 2.1 Hz, 1 H)3.29 (s, 3 H) 3.43 (d, J=3.5 Hz, 1 H) 3.49 (dd, J=10.2, 5.1 Hz, 2 H)3.56 (dd, J=10.9, 6.6 Hz, 1 H) 3.62-3.69 (m, 2 H) 3.69-3.72 (m, 4 H)3.78 (dd, J=9.0, 4.7 Hz, 1 H) 3.80-3.90 (m, 3 H) 3.97-4.06 (m, 2 H) 4.18(dd, J=6.8, 4.5 Hz, 1 H) 4.24-4.31 (m, 2 H) 4.34-4.41 (m, 1 H) 4.57 (t,J=4.7 Hz, 1 H) 4.68 (t, J=4.7 Hz, 1 H) 4.80 (s, 1 H) 4.82 (s, 1 H) 4.87(s, 1 H) 4.96 (d, J=2.0 Hz, 1 H).

dimethyl(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((triethylsilyl)oxy)propyl)-2-(((2R,4R,6S)-6-(2-((2S,5S)-5-(2-((2S,3aR,4aR,5R,6S,7S,8aR,8bS)-7-(3-hydroxypropyl)-6-((triethylsilyl)oxy)octahydro-2H-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyran-2-yl)ethyl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-4-methoxytetrahydrofuran-3-yl)-2-oxopropyl)phosphonate

To a solution of dimethyl methylphosphonate (11 μL, 0.097 mmol) in THF(0.50 mL) was added n-BuLi (1.6 M, 0.061 mL, 0.097 mmol) at −78° C., andthe resulting solution was stirred for 40 min at −78° C. A solution ofmethyl2-((2S,3S,4R,5R)-5-((S)-2,3-bis((triethylsilyl)oxy)propyl)-2-(((2R,4R,6S)-6-(2-((2S,5S)-5-(2-((3aR,4aR,5R,6S,7S,8aR,8bS)-7-(3-hydroxypropyl)-6-((triethylsilyl)oxy)octahydro-2H-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyran-2-yl)ethyl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-4-methoxytetrahydrofuran-3-yl)acetate(3.6 mg, 3.244 μmol) in THF (0.50 mL) was then added. The reactionmixture was stirred for 1.5 h at −78° C. and treated with saturatedaqueous NH₄Cl solution (2 mL). The resulting mixture was diluted withethyl acetate (2 mL) and warmed to ambient temperature. The layers wereseparated, and the aqueous layer was extracted with ethyl acetate (5mL). The combined organic layers were dried over MgSO₄, filtered,concentrated, and purified by silica gel column chromatography usingHeptane/EtOAc (1/1), EtOAc, EtOAc/MeCN (1/1), and DCM/MeOH (10/1) aseluents to provide 1 mg of the target product.

MS m/z 1202.2 [M+H]⁺, 1203.2, 1204.2. ¹H NMR (400 MHz, CDCl₃) δ ppm0.55-0.66 (m, 18 H) 0.92-0.99 (m, 27 H) 1.07 (d, J=6.6 Hz, 3 H)1.15-2.18 (m, 22 H) 2.20-2.30 (m, 1 H) 2.64-2.70 (m, 1 H) 3.07 (d, J=9.8Hz, 1 H) 3.13 (d, J=9.8 Hz, 1 H) 3.16-3.24 (m, 1 H) 3.33 (dd, J=10.2,3.5 Hz, 1 H) 3.33 (s, 3 H) 3.48-3.59 (m, 4 H) 3.63-3.72 (m, 2 H)3.73-3.88 (m, 4 H) 3.77-3.79 (m, 3 H) 3.81 (s, 3 H) 3.99-4.06 (m, 2 H)4.16-4.21 (m, 1 H) 4.26-4.31 (m, 2 H) 4.34-4.40 (m, 1 H) 4.57 (t, J=4.3Hz, 1 H) 4.68 (t, J=4.7 Hz, 1 H) 4.79 (s, 1 H) 4.84 (br. s, 1 H) 4.86(s, 1 H) 4.97 (br. s, 1 H)

Dimethyl(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((triethylsilyl)oxy)propyl)-2-(((2R,4R,6S)-6-(2-((2S,5S)-5-(2-((3aR,4aR,5R,6S,7S,8aR,8bS)-7-(3-hydroxypropyl)-6-((triethylsilyl)oxy)octahydro-2H-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyran-2-yl)ethyl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-4-methoxytetrahydrofuran-3-yl)-2-oxopropyl)phosphonate(1 mg, 0.832 μmol) was dissolved in dichloromethane and treated withsodium bicarbonate (1.4 mg, 0.017 mmol) and Dess-Martin periodinane (3.5mg, 8.3 μmol) at ambient temperature. After 2 h, the reaction mixturewas diluted with MTBE (1 mL) and water (0.5 mL). Sodium thiosulfate (3mg) was added, and the resulting mixture was stirred for 20 min atambient temperature. The layers were separated, and the aqueous layerwas extracted with EtOAc (2 mL). The combined organic layers were driedover MgSO₄ and concentrated in vacuo. The residue was diluted withtoluene and filtered through a silica gel plug, which was then rinsedwith EtOAc. The filtrate was concentrated in vacuo, and the resultingresidue was dissolved in THF (1.0 mL). A slurry mixture of zinctrifluoromethanesulfonate (2.4 mg, 0.0067 mmol), TEA (3 μL, 0.020 mmol),and TMEDA (0.5 μL, 0.0033 mmol) in THF (2 mL) was added. The resultingreaction mixture was stirred at ambient temperature for 1 day andtreated with MTBE (6 mL) and 30% aqueous NaCl (2 mL). The organic layerwas separated and washed with 30% aqueous NaCl (1.5 mL). Drying,filtration, and concentration in vacuo gave the target product. MS m/z1073.6 [M+H]⁺. The crude macrocyclic product was dissolved in THF (0.5mL) at ambient temperature and treated with 1.0 M TBAF in THF (0.020 mL,0.02 mmol). After stirring at ambient temperature overnight, formationof the target product was confirmed by LCMS analysis with an authenticsample (retention time and MS data). MS m/z 731.6 [M+H]⁺, 753.6 [M+Na]⁺.

Example 6 reparation of a Compound of Formula (VIIB)

(4R)-4-((tert-butyldimethylsilyl)oxy)-7-hydroxy-N-methoxy-N,2-dimethylheptanamide

A solution of(4R)-4-((tert-butyldimethylsilyl)oxy)-N-methoxy-N,2-dimethyl-7-oxoheptanamide(27 g, 81.4 mmol) in methanol (203 mL) was cooled to 0° C. and treatedwith NaBH₄ (1.54 g, 40.7 mmol), which was added portion wise over 30min, while maintaining the internal temperature below 10° C. Thereaction mixture was stirred at 0° C. for 2 h and quenched withsaturated aqueous NH₄Cl (67.5 mL). After stirring at room temperaturefor 20 min, the mixture was diluted with MTBE (189 mL). The organiclayer was separated, and the aqueous layer was extracted with MTBE (50mL). The organic layers were combined, washed with brine (47.3 mL), andconcentrated in vacuo. The residue was filtered through silica gel pad(ca. 40 g), which was rinsed with ethyl acetate/n-heptane=1/1 (300 mL).The filtrate was concentrated in vacuo to give the title compound (26 g,96%). ¹H NMR (400 MHz, CDCl₃) δ 0.02 (s, 6H), 0.86 (s, 9H), 1.12 (d,3H), 1.42-1.68 (m, 6H), 1.96 (m, 1H), 3.18 (s, 3H), 3.62 (m, 2H), 3.69(s, 3H), 3.75 (m, 1H).

(4R)-4-((tert-butyldimethylsilyl)oxy)-7-(methoxy(methyl)amino)-6-methyl-7-oxoheptylpivalate

A solution of(4R)-4-((tert-butyldimethylsilyl)oxy)-7-hydroxy-N-methoxy-N,2-dimethylheptanamide(26 g, 78.0 mmol) in CH₂Cl₂ (130 mL) was cooled to 0° C. and treatedwith triethylamine (19.56 mL, 140.3 mmol), TMEDA (1.18 mL, 7.80 mmol),and pivaloyl chloride (PvCl) (10.6 mL, 85.8 mmol). After stirring atroom temperature for 15 h, the mixture was treated with PvCl (0.96 mL,7.8 mmol) and triethylamine (5.43 mL, 39.0 mmol) and stirred at rt foranother 5 h. The reaction was quenched with water (260 mL). The organiclayer was separated, and the aqueous layer was extracted with MTBE (260mL). The organic layers were combined, washed with brine, and dried overMgSO₄ to give the title compound (32.07 g, 99%). ¹H NMR (400 MHz, CDCl₃)δ 0.02 (s, 6H), 0.86 (s, 9H), 1.12 (d, 3H), 1.18 (s, 9H), 1.40-1.55 (m,4H), 1.68 (m, 2H), 1.92 (m, 1H), 3.17 (s, 3H), 3.69 (m, 4H), 4.03 (t,2H).

(4R)-4-((tert-butyldimethylsilyl)oxy)-6-methyl-7-oxooctyl pivalate

A solution of(4R)-4-((tert-butyldimethylsilyl)oxy)-7-(methoxy(methyl)amino)-6-methyl-7-oxoheptylpivalate (32.07 g, 76.79 mmol) in THF (96 mL) was cooled to −20° C. andtreated with 3 M MeMgCl in THF (30.7 mL, 92.1 mmol) over 10 min, whilemaintaining the internal temperature below −10° C. The mixture waswarmed up to 0° C. over 2 h and stirred at 0° C. for 13 h. Additional 3M MeMgCl in THF (5.12 mL, 15.4 mmol) was added and stirring wascontinued at 0° C. for another 5 h. The reaction was quenched withsaturated aqueous NH₄Cl (80 mL) and extracted twice with MTBE (96 mL).The organic layers were combined, dried over MgSO₄ and concentrated invacuo to give the title compound (28.64 g, 100%). ¹H NMR (400 MHz,CDCl₃) δ 0.02 (s, 6H), 0.86 (s, 9H), 1.10 (d, 3H), 1.19 (s, 9H), 1.34(m, 1H), 1.50 (m, 2H), 1.64 (m, 2H), 1.88 (m, 1H), 2.13 (s, 3H), 2.68(m, 1H), 3.68 (m, 1H), 4.03 (t, 2H).

(4R)-4-((tert-butyldimethylsilyl)oxy)-6-methyl-7-(((trifluoromethyl)sulfonyl)oxy)oct-7-en-1-ylpivalate

A mixture of (4R)-4-((tert-butyldimethylsilyl)oxy)-6-methyl-7-oxooctylpivalate (15.0 g, 40.3 mmol) and1,1,1-trifluoro-N-phenyl-N-(trifluoromethyl)sulfonyl methanesulfonamide(21.6 g, 60.4 mmol) in THF (150 mL) was cooled to −20° C. and treatedwith 0.5 M KHMDS in toluene (105 mL, 52.3 mmol) over 20 min, whilemaintaining the internal temperature below −20° C. The mixture wasstirred at −20° C. for 1 h. Additional 0.5 M KHMDS in toluene (8.05 mL,4.03 mmol) was added, and stirring was continued at −20° C. for another1 h. The reaction was quenched with saturated aqueous NH₄Cl (105 mL) andextracted twice with n-heptane (105 mL). The organic layers werecombined, washed with brine, and concentrated in vacuo. The residue wastreated with n-heptane (80 mL) and aged in a freezer (−20° C.)overnight. The precipitate was filtered and rinsed with n-heptane. Thefiltrate was concentrated in vacuo and purified by column chromatography(ethyl acetate/n-heptane=1/20 to 1/10) to give the title compound (14.25g, 70%). ¹H NMR (400 MHz, CDCl₃) δ 0.02 (d, 6H), 0.86 (s, 9H), 1.15 (d,3H), 1.18 (s, 9H), 1.40-1.55 (m, 4H), 1.6-1.71 (m, 2H), 2.54 (m, 1H),3.74 (m, 1H), 4.03 (t, 2H), 4.90 (d, 1H), 5.09 (d, 1H).

(R)-4-((tert-butyldimethylsilyl)oxy)-6-methylocta-6,7-dien-1-yl pivalate

A mixture of Pd₂(dba)₃ (7.3 mg, 7.9 μmol) and(S)-(−)-(diphenylphosphino)-2′-methoxy-1,1′-binaphthyl (0.015 g, 0.032mmol) was purged with nitrogen and treated with n-heptane (2.0 mL). Themixture was stirred at 50° C. for 4.5 h. After cooling to roomtemperature (rt), the mixture was filtered through Celite® pad to removecatalyst, and the Celite® pad was rinsed with n-heptane. Afterconcentration, the residue was purified by column chromatography (ethylacetate/n-heptane=1/20 to 1/10) to give the title compound (130 mg,93%). ¹H NMR (400 MHz, CDCl₃) δ 0.02 (s, 6H), 0.84 (s, 9H), 1.18 (s,9H), 1.40-1.75 (m, 4H), 1.68 (t, 3H), 2.02-2.17 (m, 2H), 3.80 (m, 1H),4.03 (t, 2H), 4.55 (m, 2H).

(5S)-9-((tetrahydro-2H-pyran-2-yl)oxy)non-1-en-7-yn-5-ol

A solution of tetrahydro-2-(2-propynyloxy)-2H-pyran (27 g, 192.6 mmol)in THF (270 mL) was cooled to −78° C. and treated with 2 M n-BuLi incyclohexane (99 mL, 198.4 mmol) over 30 min, while maintaining theinternal temperature below −65° C. After stirring for 40 min at −78° C.,to the mixture was added BF₃.OEt₂ (25.1 mL, 198.4 mmol) over 5 min, theresulting mixture was stirred at −78° C. for 15 min. A solution of(S)-2-(but-3-en-1-yl)oxirane (20.79 g, 211.9 mmol) in THF (54.0 mL) wasadded over 30 min, while maintaining the internal temperature below −65°C., and stirring was continued at −78° C. for 1 h. The reaction wasquenched with saturated aqueous NH₄Cl (270 mL) and warmed to rt. Theorganic layer was separated and the aqueous layer was extracted withMTBE (270 mL). The organic layers were combined, washed with saturatedaqueous NaHCO₃ (81 mL) and brine (80 mL), and dried over MgSO₄ to givethe title compound (40.1 g, 87%). ¹H NMR (400 MHz, CDCl₃) δ 1.45-1.88(m, 7H), 2.00-2.30 (m, 3H), 2.34-2.50 (m, 2H), 3.51 (m, 1H), 3.70-3.88(m, 2H), 4.25 (m, 2H), 4.80 (m, 1H), 5.00 (m, 2H), 5.81 (m, 1H).

(4S)-4-hydroxy-8-((tetrahydro-2H-pyran-2-yl)oxy)oct-6-ynal

A mixture of (5S)-9-((tetrahydro-2H-pyran-2-yl)oxy)non-1-en-7-yn-5-ol(38 g, 159.4 mmol), 1,4-dioxane (798 mL), and water (266 mL) was treatedwith sodium periodate (136 g, 637.8 mmol) and 2,6-lutidine (37.1 mL,319.0 mmol). The mixture was cooled with an ice-bath and treated withOsO₄ (0.020 g, 0.08 mmol); the ice-bath was removed, and the mixture wasstirred at room temperature (rt) for 20 min. Additional OsO₄ (0.020 g,0.08 mmol) was added, and stirring was continued at rt for another 6 h.The mixture was diluted with water (1824 mL) and CH₂Cl₂ (836 mL). Theorganic layer was separated, and the aqueous layer was extracted withCH₂Cl₂ (836 mL). The organic layers were combined, dried over MgSO₄, andconcentrated in vacuo to give the title compound (55 g, 144%).

(4S)-8-((tetrahydro-2H-pyran-2-yl)oxy)oct-6-yne-1,4-diol

A solution of (4S)-4-hydroxy-8-((tetrahydro-2H-pyran-2-yl)oxy)oct-6-ynal(55 g, 160 mmol) in methanol (308 mL) was cooled to 0° C. and treatedwith sodium borohydride (1.818 g, 48.066 mmol), which was added portionwise. After stirring at 0° C. for 1 h, additional sodium borohydride(0.606 g, 16.0 mmol) was added in two portions with a 0.5 h interval,and stirring was continued at 0° C. for another 0.5 h. The reaction wasquenched with saturated aqueous NH₄Cl (308 mL) and stirred at roomtemperature (rt) for 0.5 h. The mixture was extracted sequentially withMTBE (308 mL×2) and ethyl acetate (308 mL×2). The organic layers werecombined and washed with brine (116 mL). After concentration, theresidue was loaded on silica gel pad and eluted with MTBE (ca. 600 mL).The filtrate was concentrated in vacuo to give the title compound (33.66g, 87%). ¹H NMR (400 MHz, CDCl₃) δ 1.48-1.86 (m, 10H), 2.34-2.50 (m,2H), 3.51 (m, 1H), 3.60-3.72 (m, 2H), 3.72-3.88 (m, 2H), 4.25 (m, 2H),4.80 (m, 1H).

(4S)-4-hydroxy-8-((tetrahydro-2H-pyran-2-yl)oxy)oct-6-yn-1-yl pivalate

A solution of (4S)-8-((tetrahydro-2H-pyran-2-yl)oxy)oct-6-yne-1,4-dial(15.0 g, 61.9 mmol) in CH₂Cl₂ (120 mL) was treated with 2,4,6-collidine(34.4 mL, 260 mmol) and cooled to 0° C. After addition of pivaloylchloride (8.38 mL, 68.094 mmol) and DMAP (0.378 g, 3.095 mmol), themixture was stirred at 0° C. for 4.5 h. The reaction was quenched withwater (105 mL) and extracted twice with MTBE (105 mL). The organiclayers were combined, washed with 1 N HCl (105 mL) and brine (45.0 mL),and concentrated in vacuo to give the title compound (22 g, 109%). ¹HNMR (400 MHz, CDCl₃) δ 1.21 (s, 9H), 1.48-1.86 (m, 10H), 2.30-2.50 (m,2H), 3.52 (m, 1H), 3.72-3.86 (m, 2H), 4.06 (m, 2H), 4.16-4.32 (m, 2H),4.79 (m, 1H).

(S)-4,8-dihydroxyoct-6-yn-1-yl pivalate

A solution of(4S)-4-hydroxy-8-((tetrahydro-2H-pyran-2-yl)oxy)oct-6-yn-1-yl pivalate(22 g, 67.4 mmol) in methanol (110 mL) was treated with p-TsOH (0.641 g,3.37 mmol). After being stirred at rt for 5.5 h, the mixture was treatedwith saturated aqueous NaHCO₃ (56.6 mL) and concentrated in vacuo. Theresidue was sequentially extracted with MTBE (154 mL) and ethyl acetate(154 mL×2). The organic layers were combined and washed with brine.After concentration, the residue was purified by silica gel columnchromatography (ethyl acetate/n-heptane=1/10 to 3/2) to give the titlecompound (7.2 g, 37% for 5 steps). ¹H NMR (400 MHz, CDCl₃) δ 1.19 (s,9H), 1.55-1.63 (m, 2H), 1.63-1.83 (m, 2H), 2.35 (m, 1H), 2.47 (m, 1H),3.77 (m, 1H), 4.08 (t, 2H), 4.25 (m, 2H).

(S)-4-hydroxy-8-((mesitylsulfonyl)oxy)oct-6-yn-1-yl pivalate

A 0° C., a mixture of (S)-4,8-dihydroxyoct-6-yn-1-yl pivalate (6.67 g,27.527 mmol), benzyltriethylammonium chloride (0.313 g, 1.38 mmol),toluene (66.7 mL), and 15% aqueous NaOH (66.7 mL, 250 mmol) was treatedwith 2-mesitylenesulfonyl chloride (MtsCl) (3.61 g, 16.5 mmol) intoluene (40.0 mL) over 20 min, while maintaining the internaltemperature below 5° C. The mixture was stirred at 0° C. for another 1h. The organic layer was separated, and the aqueous layer was extractedwith MTBE (74.1 mL). The organic layers were combined and dried overMgSO₄. After concentration, the residue was purified by silica gelcolumn chromatography (ethyl acetate/n-heptane=1/10 to 5/3) to give thetitle compound (2.49 g, 21%). ¹H NMR (400 MHz, CDCl₃) δ 1.19 (s, 9H),1.45-1.55 (m, 2H), 1.55-1.83 (m, 4H), 2.30 (s, 3H), 2.62 (s, 6H), 3.65(m, 1H), 4.08 (t, 2H), 4.69 (m, 2H), 6.99 (s, 2H).

(S)-4-hydroxy-6-methylocta-6,7-dien-1-yl pivalate

A suspension of copper(I) cyanide (0.788 g, 8.80 mmol) in THF (21.4 mL)was cooled to −78° C. and treated with 1.6 M MeLi in diethyl ether (5.50mL, 8.80 mmol) over 20 min, while maintaining the internal temperaturebelow −60° C. The mixture was stirred −78° C. for 20 min and warmed to0° C. over 40 min. The mixture was cooled to −78° C., stirred foranother 10 min, and treated with a solution of(S)-4-hydroxy-8-((mesitylsulfonyl)oxy)oct-6-yn-1-yl pivalate (2.49 g,5.87 mmol) in THF (10.7 mL) over 20 min, while maintaining the internaltemperature below −65° C. After stirring at −78° C. for 1 h, thereaction was quenched with a mixture of saturated aqueous NH₄Cl (37.4mL) and 28% aqueous NH₄OH (4.98 mL), and warmed to room temperature(rt). The organic layer was separated, and the aqueous layer wasextracted twice with MTBE (24.90 mL). The organic layers were combinedand washed with brine. After concentration, the residue was purified bysilica gel column chromatography (ethyl acetate/n-heptane=1/10 to 1/3)to give the title compound (1.136 g, 81%). ¹H NMR (400 MHz, CDCl₃) δ1.28 (s, 9H), 1.48-1.56 (m, 2H), 1.65-1.75 (m, 3H), 1.75-1.85 (m, 2H),2.00-2.13 (m, 2H), 3.78 (m, 1H), 4.08 (m, 2H), 4.68 (m, 2H).

(S)-2-bromo-7-((tert-butyldiphenylsilyl)oxy)hept-1-en-4-yl acetate

A solution of (S)-2-bromo-7-((tert-butyldiphenylsilyl)oxy)hept-1-en-4-ol(6.0 g, 13.408 mmol) in CH₂Cl₂ (48.0 mL) was treated with triethylamine(3.74 mL, 26.8 mmol), acetic anhydride (1.52 mL, 16.1 mmol), and DMAP(0.164 g, 1.34 mmol). After stirring at room temperature (rt) for 20 h,the reaction was quenched with water (30.0 mL) and diluted with MTBE(30.0 mL). The organic layer was separated and washed with brine. Afterconcentration, the residue was purified by silica gel columnchromatography (ethyl acetate/n-heptane=1/20 to 1/8) to give the titlecompound (5.254 g, 80%). ¹H NMR (400 MHz, CDCl₃) δ 1.05 (s, 9H),1.52-1.70 (m, 3H), 1.76 (m, 1H), 2.02 (s, 3H), 2.60 (dd, 1H), 2.73 (dd,1H), 3.68 (m, 2H), 5.19 (m, 1H), 5.49 (s, 1H), 5.63 (s, 1H), 7.39 (m,6H), 7.65 (m, 4H).

(S)-8-((tert-butyldiphenylsilyl)oxy)-5-hydroxy-3-methyleneoctan-2-one

A solution of(S)-N-(2-(4-isopropyl-4,5-dihydrooxazol-2-yl)-6-methylphenyl)methanesulfonamide(2.44 g, 8.23 mmol) in a degassed THF (26.0 mL) was treated withchromium(II) chloride (1.01 g, 8.23 mmol), purged with nitrogen for 5min, and heated to 30° C. After addition of triethylamine (1.15 mL, 8.23mmol), the mixture was stirred at 30-35° C. for 1 h. The mixture wascooled to 0° C., treated with nickel(II) chloride2,9-dimethyl-1,10-phenanthroline complex (0.090 g, 0.27 mmol), purgedwith nitrogen for 5 min, and then treated with a solution of(S)-2-bromo-7-((tert-butyldiphenylsilyl)oxy)hept-1-en-4-yl acetate (1.3g, 2.7 mmol) in THF (10 mL) (8 mL+2 mL rinse). The mixture was stirredat 0° C. for 10 min and at rt for 2 h. The reaction mixture was treatedwith Florisil® (5.8 g) and stirred at rt for 30 min. The mixture wasdiluted with n-heptane (19.5 mL), filtered through florisil pad andrinsed with MTBE (19.5 mL). The filtrate was washed with water (13 mL)and brine (6.50 mL). After concentration, the residue was purified bycolumn chromatography (ethyl acetate/n-heptane=1/10 to 1/2) to give thetitle compound (613 mg, 56%). ¹H NMR (400 MHz, CDCl₃) δ 1.01 (s, 9H),1.42-1.70 (m, 4H), 2.32 (dd, 1H), 2.36 (s, 3H), 2.55 (m, 1H), 3.69 (m,3H), 5.90 (s, 1H), 6.11 (s, 1H), 7.39 (m, 6H), 7.65 (m, 4H).

(S)-5-((tert-butyldimethylsilyl)oxy)-8-((tert-butyldiphenylsilyl)oxy)-3-methyleneoctan-2-one

A solution of(S)-8-((tert-butyldiphenylsilyl)oxy)-5-hydroxy-3-methyleneoctan-2-one(0.643 g, 1.57 mmol) in DMF (5.14 mL) was treated with TBSCl (0.283 g,1.88 mmol) and imidazole (0.213 g, 3.13 mmol). The mixture was stirredat rt for 4.5 h. The reaction was quenched with water (12.86 mL) andextracted twice with MTBE (19.29 mL). The organic layers were combined,and washed with water (12.9 mL) and brine (6.43 mL). Afterconcentration, the residue was purified by column chromatography (ethylacetate/n-heptane=1/10 to 1/8) to give the title compound (456 mg, 56%).¹H NMR (400 MHz, CDCl₃) δ 0.00 (s, 6H), 0.88 (s, 9H), 1.03 (s, 9H),1.42-1.70 (m, 4H), 2.31 (s, 3H), 2.32 (dd, 1H), 2.44 (dd, 1H), 3.63 (t,2H), 3.79 (m, 1H), 5.81 (s, 1H), 6.04 (s, 1H), 7.39 (m, 6H), 7.66 (m,4H).

(S)-2,2,3,3,11,11-hexamethyl-5-(2-methylbuta-2,3-dien-1-yl)-10,10-diphenyl-4,9-dioxa-3,10-disiladodecane

A solution of(S)-5-((tert-butyldimethylsilyl)oxy)-8-((tert-butyldiphenylsilyl)oxy)-3-methyleneoctan-2-one(0.20 g, 0.381 mmol) in ethanol (2.0 mL) was treated withp-toluenesulfonyl hydrazide (0.078 g, 0.42 mmol) and stirred at rt for59 h. The resulting mixture was treated with ethanol (2.000 mL),triethylamine (0.11 mL, 0.76 mmol), and molecular sieves 4 Å (500 mg).After being stirred at 85° C. (bath) for 1 d, the mixture was filteredthrough Celite® pad to remove molecular sieves and rinsed with MTBE(20.0 mL). The filtrate was washed with water (5 mL) and brine (5 mL)and concentrated in vacuo. The residue was purified by silica gel columnchromatography (ethyl acetate/n-heptane=1/20 to 1/10) to give the titlecompound (68 mg, 35%). ¹H NMR (400 MHz, CDCl₃) δ 0.01 (s, 3H), 0.02 (s,3H), 0.87 (s, 9H), 1.04 (s, 9H), 1.42-1.66 (m, 4H), 1.68 (t, 3H),2.00-2.20 (m, 2H), 3.63 (t, 2H), 3.79 (m, 1H), 4.52 (m, 2H), 7.39 (m,6H), 7.66 (m, 4H).

Example 7 Preparation of a Compound of Formula (VIIC)

(S)-3-((2R,3R,4S,5S)-5-(2,2-dimethoxyethyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1,2-diol

A solution of2-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)acetaldehyde(20.0 g, 33.28 mmol) in methanol (100 mL) was treated with CSA (0.773 g,3.33 mmol) and stirred at rt for 3 d. The reaction was quenched withsaturated aqueous NaHCO₃ (50 mL) and extracted with MTBE (100 mL) andethyl acetate (100 mL×3). The organic layers were combined, dried overMgSO₄, and concentrated in vacuo to give the title compound (19.79 g).¹H NMR (400 MHz, CDCl₃) δ 1.80 (m, 1H), 1.85-2.00 (m, 3H), 2.56 (m, 1H),3.12 (m, 2H), 3.28 (s, 3H), 3.31 (s, 3H), 3.42 (s, 3H), 3.55 (m, 1H),3.62-3.71 (m, 2H), 3.90-3.98 (m, 3H), 4.43 (m, 1H), 7.60 (m, 2H), 7.69(m, 1H), 7.98 (m, 2H).

(S)-3-((2R,3R,4S,5S)-5-(2,2-dimethoxyethyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1,2-diyldibenzoate

A solution of(S)-3-((2R,3R,4S,5S)-5-(2,2-dimethoxyethyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1,2-diol(19.79 g, 47.29 mmol) in pyridine (99 mL, 1223.429 mmol) was cooled to0° C. and treated with benzoyl chloride (12.08 mL, 104.0 mmol). Themixture was stirred at rt for 20 h. Additional reagents were added andstirring was continued for 3 d. The reaction was quenched with water(400 mL) and extracted with MTBE (200 mL×3). The organic layers werecombined, washed with 1 N HCl (100 mL) and then with saturated aqueousNaHCO₃ (50 mL), dried over MgSO₄, and concentrated in vacuo.

The residue was dissolved in CH₂Cl₂ (297 mL) and treated withtriethylamine (26.4 mL, 189.2 mmol), benzoyl chloride (10.98 mL, 94.58mmol), and DMAP (0.289 g, 2.364 mmol). The mixture was stirred at rt for24 h. More triethylamine (23.2 mL, 166.3 mmol), benzoyl chloride (7.74mL, 66.6 mmol), and DMAP (0.578 g, 4.72 mmol) were added and stirringwas continued at rt for 7 d. The reaction was quenched with water (300mL). The organic layer was separated, and the aqueous layer wasextracted with CH₂Cl₂ (150 mL). The organic layers were combined andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (ethyl acetate/n-heptane=1/10 to 1/1) to give the titlecompound (17.82 g, 85% for two steps). ¹H NMR (400 MHz, CDCl₃) δ 1.89(m, 2H), 2.25 (m, 2H), 2.55 (m, 1H), 3.09 (m, 2H), 3.22 (s, 3H), 3.24(s, 3H), 3.42 (s, 3H), 3.59 (m, 1H), 3.89 (m, 1H), 3.92 (m, 1H), 4.39(m, 1H), 4.57 (d, 2H), 5.63 (m, 1H), 7.44 (m, 4H), 7.56 (m, 4H), 7.68(m, 1H), 7.92 (d, 2H), 8.04 (m, 4H).

(S)-3-((2R,3R,4S,5S)-3-methoxy-5-(((2R,6S)-4-methyl-3-(2-mcthoxyacctoxy)methyl-6-(3-(pivaloyloxy)propyl)-3,6-dihydro-2H-pyran-2-yl)methyl)-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1,2-diyl dibenzoate

A mixture of (S)-4-hydroxy-6-methylocta-6,7-dien-1 -yl pivalate (1.14g,4.73 mmol) and (S)-3-((2R,3R,4S,5 S)-5-(2,2-dimethoxyethyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1,2 -diyl dibenzoate (3.41 g, 5.44 mmol)was dissolved in CH₂Cl₂ (47.7 mL) and cooled to −40 ° C. The mixture wassequentially treated with methoxyacetic acid (5.44 mL, 70.9 mmol) andBF₃-OEt₂ (1.80 mL, 14.2 mmol). The mixture was warmed to −30 ° C. over 1h and stirred at −30 ° C. for 0.5 h. The reaction was quenched withsaturated aqueous NaHCO₃ (119 mL) and extracted twice with ethyl acetate(100 mL). The organic layers were combined, dried over MgSO₄ , andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (ethyl acetate/n-heptane=1/10 to 2/3) to give the titlecompound (3.61 g, 86%). ¹H NMR (400 MHz, CDCl₃) δ 1.14 (m, 1H), 1.24 (s,9H), 1.40- 1.55 (m, 3H), 1.65 (m, 1H), 1.72 (s, 3H), 1.81 (m, 1H), 1.95(m, 2H), 2.25 (m, 2H), 2.71 (m, 1H), 3.02 (dd, 1H), 3.11 (dd, 1H), 3.38(m, 1H), 3.42 (s, 6H), 3.63 (m, 1H), 3.70 (m, 1H), 3.90-4.00 (m, 3H),4.02 (d, 2H), 4.15 (m, 1H), 4.54 (d, 2H), 4.59 (d, 1H), 4.72 (d, 1H),5.59(m, 1H), 7.42 (m, 4H), 7.56 (m, 4H), 7.65 (m, 1H), 7.90 (d, 2H),8.01 (m, 4H).

(S)-3-((2R,3R,4S,5S)-3-methoxy-5-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-(pivaloyloxy)propyl)tetrahydro-2H-pyran-2-yl)methyl)-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1,2-diyl dibenzoate

A mixture of Pd(Ph₃P)₄ (0.467 g, 0.404 mmol) and triphenylphosphine(0.424 g, 1.62 mmol) in a degassed THF (36.1 mL) was heated to 60 ° C.and stirred for 5 min. The mixture was treated with a mixture of(S)-3-((2R,3R,4S,5S)-3-methoxy-5-(((2R,6S)-4-methyl-3-(2-methoxyacetoxy)methyl-6-(3-(pivaloyloxy)propyl)-3,6-dihydro-2H-pyran-2-yl)methyl)-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1,2-diyldibenzoate (3.61 g,4.04 mmol), formic acid (0.775 mL, 20.2mmol), and triethylamine (2.82mL, 20.2 mmol) in a degassed THF (36.1 mL). The mixture was stirred at60° C. for 52 h. After cooling to rt, the mixture was diluted with MTBE(36.1 mL) and washed with water (18.1 mL) and then with brine. Afterconcentration, the residue was purified by silica gel columnchromatography (ethyl acetate/n-heptane=1/10to 1/2) to give the titlecompound (2.8 g, 74% for 2 steps from allene). ¹H NMR (400 MHz, CDCl₃) δ1.00 (m, 1H), 1.05 (d, 3H), 1.14 (s, 9H), 1.38 (m, 3H), 1.61 (m, 1H),1.72 (m, 1H), 1.91 (m, 1H), 2.1-2.32 (m, 4H), 2.62 (m, 1H), 3.02 (dd,1H), 3.06 (dd, 1H), 3.36 (m, 1H), 3.42 (s, 3H), 3.66 (m, 1H), 3.72 (m,1H), 3.81 (m, 1H), 3.84-3.96 (m, 3H), 4.56 (d, 2H), 4.77 (s, 1H), 4.83(s, 1H), 5.59 (m, 1H), 7.40 (m, 4H), 7.52 (m, 4H), 7.62 (m, 1H), 7.90(m, 2H), 8.01 (m, 4H).

3-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-dihydroxypropyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)propylpivalate

A solution of(S)-3-((2R,3R,4S,5S)-3-methoxy-5-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-(pivaloyloxy)propyl)tetrahydro-2H-pyran-2-yl)methyl)-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1,2-diyldibenzoate (2.8 g, 3.5 mmol) in a mixture of THF (2.80 mL) and methanol(56.0 mL) was treated with 6-10% Mg(OMe)₂ in methanol (18.5 g, 13.9mmol). After stirring at rt for 22 h, the reaction was quenched withsaturated aqueous NH₄Cl (22.4 mL) and extracted with MTBE (56.0 mL) andethyl acetate (42.0 mL×2). The organic layers were combined and driedover MgSO₄. After concentration, the residue was azeotroped withmethanol and toluene to give a crude product, which was used for thenext step without further purification. ¹H NMR (400 MHz, CDCl₃) δ 1.02(m, 1H), 1.05 (d, 3H), 1.30 (s, 9H), 1.38 (m, 3H), 1.61 (m, 1H), 1.72(m, 1H), 1.85 (m, 1H), 1.90-2.03 (m, 2H), 2.05-2.27 (m, 2H), 2.67 (m,1H), 3.05 (bd, 1H), 3.23 (dd, 1H), 3.42 (s, 3H), 3.45 (m, 1H), 3.60 (m,1H), 3.70 (m, 1H), 3.75 (m, 1H), 3.80-4.01 (m, 5H), 4.10 (m, 1H), 4.80(s, 1H), 4.88 (s, 1H), 7.60 (m, 2H), 7.62 (m, 1H), 7.95 (m, 2H).

3-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)propylpivalate

A solution of3-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-dihydroxypropyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)propylpivalate (2.07 g, 3.469 mmol) in DMF (16.56 mL, 213.871 mmol) wastreated with imidazole (0.945 g, 13.9 mmol) and TBSCl (1.20 g, 7.98mmol). The mixture was stirred at rt for 1 h. Additional imidazole(0.945 g, 13.9 mmol) and TBSCl (1.20 g, 7.98 mmol) were added, andstirring was continued at rt for another 18 h. The reaction was quenchedwith water (41.4 mL) and extracted with MTBE (41.4 mL×2). The organiclayers were combined and dried over MgSO₄. After concentration, theresidue was purified by silica gel column chromatography (1/10 to 1/5)to give the title compound (3.115 g, 109%). ¹H NMR (400 MHz, CDCl₃) δ0.03 (s, 6H), 0.09 (s, 6H), 0.91 (s, 18H), 1.02 (m, 1H), 1.05 (d, 3H),1.15 (s, 9H), 1.40 (m, 3H), 1.61 (m, 1H), 1.72 (m, 1H), 1.82 (m, 1H),1.90 (m, 1H), 1.99 (m, 1H), 2.15-2.27 (m, 2H), 2.58 (m, 1H), 3.02 (m,2H), 3.39 (m, 1H), 3.40 (s, 3H), 3.45 (m, 1H), 3.55 (m, 1H), 3.65 (m,2H), 3.75-3.85 (m, 3H), 3.85-4.0 (m, 2H), 4.79 (s, 1H), 4.88 (s, 1H),7.60 (m, 2H), 7.62 (m, 1H), 7.92 (m, 2H).

3-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)propan-1-ol

A solution of3-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)propylpivalate (3.11 g, 3.77 mmol) in CH₂Cl₂ (31.1 mL) was cooled to −78° C.and treated with 1M DIBAL in toluene (8.29 mL, 8.29 mmol). The mixturewas stirred at −78° C. for 1 h. Additional 1M DIBAL in toluene (1.507mL, 1.507 mmol) was added, and stirring was continued for another 1.5 h.After quenching the reaction with methanol (1.53 mL, 37.7 mmol), themixture was treated with 1 N HCl (37.7 mL) and stirred at rt for 1 h.The mixture was extracted with MTBE (31.1 mL×2). The organic layers werecombined, washed with saturated aqueous NaHCO₃ (15.6 mL), dried overMgSO₄, and concentrated in vacuo to give the title compound (2.9 g,104%). ¹H NMR (400 MHz, CDCl₃) δ 0.03 (s, 6H), 0.09 (s, 6H), 0.88 (s,18H), 1.08 (m, 1H), 1.08 (d, 3H), 1.48 (m, 3H), 1.63 (m, 1H), 1.72 (m,1H), 1.82 (m, 1H), 1.88-2.02 (m, 2H), 2.12-2.27 (m, 2H), 2.58 (m, 1H),3.03 (dd, 1H), 3.10 (dd, 1H), 3.40 (s, 3H), 3.42-3.50 (m, 2H), 3.55 (m,3H), 3.68 (m, 2H), 3.80 (m, 3H), 4.79 (s, 1H), 4.88 (s, 1H), 7.60 (m,2H), 7.62 (m, 1H), 7.97 (m, 2H).

(S)-5-(((2R,3R,4S,5S)-3-methoxy-5-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-((triethylsilyl)oxy)propyl)tetrahydro-2H-pyran-2-yl)methyl)-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane

A solution of3-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)propan-1-ol(2.9 g, 3.9 mmol) in CH₂Cl₂ (29.0 mL) was treated with triethylamine(1.09 mL, 7.83 mmol) and chlorotriethylsilane (0.799 mL, 4.70 mmol).After stirring at rt for 17 h, the reaction was quenched with water(29.0 mL) and extracted twice with MTBE (29.0 mL). The organic layerswere combined and washed with brine. After concentration, the residuewas purified by silica gel column chromatography (ethylacetate/n-heptane=1/20 to 1/5) to give the title compound (2.95 g, 88%).¹H NMR (400 MHz, CDCl₃) δ 0.03 (s, 6H), 0.04 (s, 6H), 0.56 (q, 6H),0.82-1.00 (m, 27H), 1.02 (m, 1H), 1.06 (d, 3H), 1.30-1.52 (m, 4H), 1.74(m, 1H), 1.78-1.90 (m, 2H), 2.00 (m, 1H), 2.15-2.23 (m, 2H), 2.56 (m,1H), 2.96-3.10 (m, 2H), 3.35 (m, 1H), 3.43 (s, 3H), 3.43-3.62 (m, 5H),3.68 (m, 1H), 3.79 (m, 2H), 3.83 (m, 1H), 4.78 (s, 1H), 4.85 (s, 1H),7.60 (m, 2H), 7.62 (m, 1H), 7.96 (m, 2H).

Example 7 Preparation of a Compound of Formula (VD)

(R)-2-bromo-7-((tert-butyldiphenylsilyl)oxy)hept-1-en-4-yl benzoate

A solution of (S)-2-bromo-7-((tert-butyldiphenylsilyl)oxy)hept-1-en-4-ol(25.0 g, 55.9 mmol) in toluene (200 mL) was treated with benzoic acid(8.19 g, 67.0 mmol) and triphenylphosphine (17.58 g, 67.0 mmol). Aftercooling to 0° C., the mixture was treated with DEAD (24.32 mL, 61.46mmol) over 20 min, while maintaining the internal temperature below 6°C. and stirred at 0° C. for 2 h. The mixture was treated with n-heptane(83 mL) and stirred at 0° C. for 30 min. The precipitate was filteredand washed with n-heptane (83 mL). The filtrate was concentrate in vacuoto give the title compound (46.6 g).

(R)-2-bromo-7-hydroxyhept-1-en-4-yl benzoate

A solution of (R)-2-bromo-7-((tert-butyldiphenylsilyl)oxy)hept-1-en-4-ylbenzoate (30.8 g, 55.8 mmol) in acetonitrile (200 mL) was treated with48% HF in water (10.1 mL, 279 mmol) and stirred at rt for 13 h. Thereaction was quenched with saturated aqueous NaHCO₃ (308 mL) and dilutedwith MTBE (154 mL). The organic layer was separated, and the aqueouslayer was extracted with MTBE (154 mL). The organic layers were combinedand washed with brine. After concentration, the residue was purified bysilica gel column chromatography (ethyl acetate/n-heptane=1/10 to 1/2)to give the title compound (14.67 g, 84%). ¹H NMR (400 MHz, CDCl₃) δ1.29 (m, 1H), 1.61-1.71 (m, 2H), 1.75-1.90 (m, 2H), 2.73 (dd, 1H), 2.90(dd, 1H), 3.69 (t, 2H), 5.46 (m, 1H), 5.48 (s, 1H), 5.69 (s, 1H), 7.41(m, 2H), 7.58 (m, 1H), 8.02 (m, 2H).

(R)-2-bromo-7-oxohept-1-en-4-yl benzoate

A solution of 2 M oxalyl chloride in CH₂Cl₂ (6.96 mL, 13.9 mmol) inCH₂Cl₂ (21.80 mL) was cooled to −78° C. and treated with DMSO (1.976 mL,27.843 mmol), while maintaining the internal temperature below −60° C.After stirring at −78° C. for 10 min, a solution of(R)-2-bromo-7-hydroxyhept-1-en-4-yl benzoate (2.18 g, 6.961 mmol) inCH₂Cl₂ (10.90 mL) was added, and stirring was continued at −78° C. for30 min. Triethylamine (9.70 mL, 69.6 mmol) was added, while maintainingthe internal temperature below −60° C. Then, the mixture was stirred at−78° C. for 10 min and 0° C. for 30 min. The mixture was treated withwater (21.80 mL) and extracted twice with MTBE (32.7 mL). The organiclayers were combined, and washed with water (21.80 mL) and brine. Afterconcentration, the residue was purified by silica gel columnchromatography (ethyl acetate/n-heptane=1/10 to 1/3) to give the titlecompound (1.477 g, 68%). ¹H NMR (400 MHz, CDCl₃) δ 2.04 (m, 1H), 2.14(m, 1H), 2.60 (m, 2H), 2.73 (dd, 1H), 2.92 (dd, 1H), 5.45 (m, 1H), 5.50(s, 1H), 5.70 (s, 1H), 7.43 (m, 2H), 7.58 (m, 1H), 8.02 (m, 2H), 9.79(s, 1H).

2-((2R,4aS,6S,7R,8S,8aS)-7,8-bis((tert-butyldimethylsilyl)oxy)-6-((S,E)-1-((tert-butyldimethylsilyl)oxy)-3-iodoallyl)octahydropyrano[3,2-b]pyran-2-yl)ethanol

Methyl2-((2R,4aS,6S,7R,8S,8aS)-7,8-bis((tert-butyldimethylsilyl)oxy)-6-((S,E)-1-((tert-butyldimethylsilyl)oxy)-3-iodoallyl)octahydropyrano[3,2-b]pyran-2-yl)acetate(90.0 g, 31.5 mmol, a solution in toluene, ca. 27%) was diluted withtoluene (316 mL) and cooled to −78° C. The mixture was treated with 1MDIBAL in toluene (37.8 mL, 37.8 mmol) and stirred at −78° C. for 1 h.After removing the cold bath, the reaction was quenched with methanol(7.65 mL, 189 mmol) and treated with 1 N HCl (243 mL, 243 mmol) and MTBE(170 mL). After stirring at rt for 30 min, the organic layer wasseparated, and the aqueous layer was extracted with MTBE (170 mL). Theorganic layers were combined, washed sequentially with 1 N HCl (122 mL),water (122 mL), saturated aqueous NaHCO₃ (122 mL), and brine (120 mL).

After concentration, the residue was dissolved in methanol (194 mL),cooled to 0° C., and treated with sodium borohydride (0.596 g, 15.8mmol). The reaction mixture was stirred at 0° C. for 1 h and quenchedwith 1 N HCl (63.0 mL, 63.0 mmol). After dilution with MTBE (365 mL),the organic layer was separated and washed sequentially with 1 N HCl(63.0 mL) and saturated aqueous NaHCO₃ (122 mL) (with brine). Theorganic layer was dried over MgSO₄ and concentrated in vacuo to give thetitle compound (23.44 g, 100%).

(((2S,3R,4S,4aS,6R,8aS)-2-((S,E)-1-((tert-butyldimethylsilyl)oxy)-3-iodoallyl)-6-(2-((triethylsilyl)oxy)ethyl)octahydropyrano[3,2-b]pyran-3,4-diyl)bis(oxy))bis(tert-butyldimethylsilane)

A solution of2-((2R,4aS,6S,7R,8S,8aS)-7,8-bis((tert-butyldimethylsilyl)oxy)-6-((S,E)-1-((tert-butyldimethylsilyl)oxy)-3-iodoallyl)octahydropyrano[3,2-b]pyran-2-yl)ethanol (23.44 g, 31.548 mmol) inCH₂Cl₂ (211 mL) was treated with chlorotriethylsilane (6.44 mL, 37.9mmol) and triethylamine (8.79 mL, 63.1 mmol), and stirred at rt for 3 h.Additional chlorotriethylsilane (1.06 mL, 6.31 mmol) and triethylamine(1.32 mL, 9.46 mmol) were added, and stirring was continued at rt foranother 8 h. The reaction was quenched with water (117 mL). The organiclayer was separated, and the aqueous layer was extracted with MTBE (117mL). The organic layers were combined, and dried over MgSO₄. Afterconcentration, the residue was purified by silica gel columnchromatography (ethyl acetate/n-heptane=1/20 to 1/10) to give the titlecompound (23.7 g, 95%). ¹H NMR (400 MHz, CDCl₃) δ 0.02 (s, 3H), 0.03 (s,3H), 0.10 (s, 3H), 0.11 (s, 3H), 0.12 (s, 3H), 0.14 (s, 3H), 0.59 (q,6H), 0.86 (s, 9H), 0.9-1.0 (m, 27 H), 1.25-1.35 (m, 2H), 1.60-1.72 (m,3H), 1.92 (m, 1H), 2.84 (d, 1H), 3.45 (m, 2H), 3.58 (m, 1H), 3.73 (m,1H), 3.83 (dd, 1H), 3.89 (dd, 1H), 4.09 (m, 1H), 4.91 (m, 1H), 6.29 (d,1H), 6.85 (dd, 1H).

(4R,10S,E)-10-((2S,3R,4S,4aS,6R,8aS)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(2-((triethylsilyl)oxy)ethyl)octahydropyrano[3,2-b]pyran-2-yl)-2-bromo-10-((tert-butyldimethylsilyl)oxy)-7-hydroxydeca-1,8-dien-4-ylbenzoate

A solution of(((2S,3R,4S,4aS,6R,8aS)-2-((S,E)-1-((tert-butyldimethylsilyl)oxy)-3-iodoallyl)-6-(2-((triethylsilyl)oxy)ethyl)octahydropyrano[3,2-b]pyran-3,4-diyl)bis(oxy))bis(tert-butyldimethylsilane)(4.48 g, 5.22 mmol) in THF (32.5 mL) was cooled to −78° C. and treatedwith 1.6 M n-BuLi in n-hexane (3.26 mL, 5.22 mmol), while maintainingthe internal temperature below −65° C. After stirring at −78° C. for 20min, the mixture was treated with a solution of magnesium bromidediethyl etherate (1.35 g, 5.22 mmol) in THF (16.25 mL), whilemaintaining the internal temperature below −65° C., and stirred at −78°C. for 30 min. A solution of (R)-2-bromo-7-oxohept-1-en-4-yl benzoate(1.477 g, 4.747 mmol) and magnesium bromide diethyl etherate (1.35 g,5.22 mmol) in THF (18.3 mL) was added, and the resulting mixture wasstirred at −78° C. for 10 min, slowly warmed to −25° C. over 4 h andstirred at −25° C. for 1 h. The reaction was quenched with saturatedaqueous NH₄Cl (29.5 mL) and extracted twice with MTBE (29.5 mL). Theorganic layers were combined and washed with brine. After concentration,the residue was purified by silica gel column chromatography (ethylacetate/n-heptane=1/10 to 1/5) to give the title compound (3.35 g, 68%).

(4R,10S,E)-10-((2S,3R,4S,4aS,6R,8aS)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(2-((triethylsilyl)oxy)ethyl)octahydropyrano[3,2-b]pyran-2-yl)-2-bromo-10-((tert-butyldimethylsilyl)oxy)-7-oxodeca-1,8-dien-4-ylbenzoate

A solution of(4R,10S,E)-10-((2S,3R,4S,4aS,6R,8aS)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(2-((triethylsilyl)oxy)ethyl)octahydropyrano[3,2-b]pyran-2-yl)-2-bromo-10-((tert-butyldimethylsilyl)oxy)-7-hydroxydeca-1,8-dien-4-ylbenzoate (3.35 g, 3.213 mmol) in CH₂Cl₂ (33.5 mL) was treated withsodium bicarbonate (0.540 g, 6.43 mmol) and Dess-Martin periodinane(1.64 g, 3.86 mmol). The mixture was stirred at rt for 1 h. The reactionwas quenched with saturated aqueous NaHCO₃ (25.1 mL) and 20% Na₂SO₃(25.1 mL) and extracted twice with MTBE (26.8 mL). The organic layerswere combined and washed with brine (16.75 mL). After concentration, theresidue was purified by silica gel column chromatography (ethylacetate/n-heptane=1/20 to 1/8) to give the title compound (2.26 g, 68%).¹H NMR (400 MHz, CDCl₃) δ 0.07 (s, 3H), 0.02 (s, 3H), 0.11 (s, 6H), 0.12(s, 3H), 0.13 (s, 3H), 0.60 (q, 6H), 0.82 (s, 9H), 0.88 (t, 9H), 0.92(s, 9H), 0.94 (s, 9H), 1.05-1.25 (m, 3H), 1.48-1.60 (m, 3H), 1.70 (m,1H), 2.00-2.20 (m, 2H), 2.69 (m, 2H), 2.72 (dd, 1H), 2.82 (d, 2H), 2.91(dd, 1H), 3.29 (m, 1H), 3.42 (m, 1H), 3.63 (m, 1H), 3.72 (m, 1H), 3.91(m, 2H), 4.10 (bs, 1H), 5.11 (m, 1H), 5.43 (m, 1H), 5.49 (d, 1H), 5.68(s, 1H), 6.29 (d, 1H), 7.08 (dd, 1H), 7.41 (m, 2H), 7.52 (m, 1H), 8.01(m, 2H).

(R)-2-bromo-8-((2R,3S,3aS,4aS,7R,8aR,9S,9aS)-3,9-dihydroxy-7-(2-hydroxyethyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-2-yl)-7-oxooct-1-en-4-ylbenzoate

A mixture of imidazole hydrochloride (0.704 g, 6.73 mmol) and 1 M TBAFin THF (14.12 mL, 14.1 mmol) in THF (45.2 mL) was treated with asolution of(4R,10S,E)-10-((2S,3R,4S,4aS,6R,8aS)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(2-((triethylsilyl)oxy)ethyl)octahydropyrano[3,2-b]pyran-2-yl)-2-bromo-10-((tert-butyldimethylsilyl)oxy)-7-oxodeca-1,8-dien-4-ylbenzoate (2.26 g, 2.17 mmol) in THF (31.6 mL). The mixture was stirredat rt for 7 d. The mixture was treated with toluene (56.5 mL) and water(56.5 mL). The organic layer was separated, and the aqueous layer wasextracted twice with a mixture of toluene (38.4 mL) and THF (38.4 mL).The organic layers were combined, concentrated in vacuo and thenazeotroped three times with acetonitrile (18.1 mL) to give the titlecompound (1.4 g).

(R)-5-bromo-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(2-hydroxyethyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2-yl)hex-5-en-3-ylbenzoate

A solution of(R)-2-bromo-8-((2R,3S,3aS,4aS,7R,8aR,9S,9aS)-3,9-dihydroxy-7-(2-hydroxyethyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-2-yl)-7-oxooct-1-en-4-ylbenzoate (1.27 g, 2.17 mmol) in CH₂Cl₂ (68.4 mL) was treated with PPTS(3.00 g, 11.9 mmol) and stirred at rt for 23 h. After concentration, theresidual solid (PPTS) was treated with ethyl acetate (50.7 mL), stirredat rt for 10 min, filtered, and rinsed with ethyl acetate. The filtratewas concentrated, treated again with ethyl acetate (10.14 mL), andstirred at rt for 2 h. The precipitate was filtered, washed with ethylacetate (3 mL), and dried under N₂ purge to give the title compound(1^(st) crop, 495 mg, contaminated with 14% PPTS).

The filtrate was treated with ethyl acetate (ca. 3 mL) at 40° C. andstirred at ambient temperature for 2 h. The precipitate was filtered,washed with ethyl acetate (1 mL), and dried under N₂ purge to give thetitle compound (2^(nd) crop, 175 mg, total 47% (1^(st) and 2^(nd) cropscombined) for 2 steps). ¹H NMR (400 MHz, CDCl₃) δ 1.30-1.50 (m, 2H),1.65-2.16 (m, 10H), 2.79 (m, 1H), 2.86-2.94 (m, 2H), 3.61 (m, 1H),3.70-3.84 (m, 2H), 4.05 (dd, 1H), 4.19 (dd, 1H), 4.27 (m, 1H), 4.42 (m,1H), 4.60 (dd, 1H), 4.68 (dd, 1H), 5.40 (m, 1H), 5.47 (s, 1H), 5.68 (s,1H), 7.41 (m, 2H), 7.57 (m, 1H), 8.03 (m, 2H).

(R)-5-bromo-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(2-oxoethyl)decahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2(3H)-yl)hex-5-en-3-ylbenzoate

A mixture of(R)-5-bromo-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(2-hydroxyethyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2-yl)hex-5-en-3-ylbenzoate (0.49 g, 0.87 mmol) and sodium bicarbonate (0.182 g, 2.17 mmol)in CH₂Cl₂ (4.9 mL) was treated with Dess-Martin periodinane (0.551 g,1.30 mmol), and stirred at rt for 2 h. The reaction was quenched with20% Na₂SO₃ (2.5 mL) and saturated aqueous NaHCO₃ (2.5 mL). The mixturewas extracted three times with MTBE (4.9 mL) and ethyl acetate (4.9 mL).The combined organic layers were dried over MgSO₄ and concentrated invacuo.

The residue was dissolved in ethyl acetate (ca. 3 mL) with heating andslowly cooled to rt over 20 h. The precipitate was filtered, washed withethyl acetate (1 mL), and dried under N₂ purge for 2 h to give the titlecompound (216 mg, 44%) along with 200 mg from the filtrate. ¹H NMR (400MHz, CDCl₃) δ 1.40 (m, 2H), 1.77 (m, 1H), 1.86 (m, 1H), 1.92-2.16 (m,6H), 2.48 (m, 1H), 2.73 (m, 1H), 2.78 (m, 1H), 2.87-2.95 (m, 2H), 3.89(m, 1H), 4.08 (dd, 1H), 4.20 (dd, 1H), 4.28 (m, 1H), 4.43 (m, 1H), 4.51(dd, 1H), 4.69 (dd, 1H), 5.46 (m, 1H), 5.48 (s, 1H), 5.68 (s, 1H), 7.43(m, 2H), 7.55 (m, 1H), 8.03 (m, 2H), 9.79 (s, 1H).

(3R)-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-((triethylsilyl)oxy)propyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)-2-hydroxy-3-(phenylsulfonyl)propyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2-yl)-5-bromohex-5-en-3-ylbenzoate

A solution of(S)-5-(((2R,3R,4S,5S)-3-methoxy-5-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-((triethylsilyl)oxy)propyl)tetrahydro-2H-pyran-2-yl)methyl)-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane(0.478 g, 0.559 mmol) in THF (4.2 mL) was cooled to −5° C. The mixturewas treated with 1.6 M n-BuLi in n-hexane (0.349 mL, 0.559 mmol) andstirred at −5° C. for 30 min. After cooling to −78° C., the mixture wastreated with a solution of(R)-5-bromo-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(2-oxoethyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2-yl)hex-5-en-3-ylbenzoate (0.21 g, 0.373 mmol) in a mixture of n-heptane (1.1 mL) and THF(3.2 mL), while maintaining the internal temperature below −65° C. Afterstirring at −78° C. for 4 h, the reaction was quenched with saturatedaqueous NH₄Cl (5 mL) and extracted three times with MTBE (10 mL). Theorganic layers were combined, dried over MgSO₄ and concentrated in vacuoto give the title compound (690 mg, 130%).

(R)-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-((triethylsilyl)oxy)propyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)-2-oxo-3-(phenylsulfonyl)propyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2-yl)-5-bromohex-5-en-3-ylbenzoate

A solution of(3R)-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-((triethylsilyl)oxy)propyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)-2-hydroxy-3-(phenylsulfonyl)propyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2-yl)-5-bromohex-5-en-3-ylbenzoate (0.69 g, 0.49 mmol) in CH₂Cl₂ (6.9 mL) was treated with sodiumbicarbonate (0.061 g, 0.73 mmol) and Dess-Martin periodinane (0.248 g,0.584 mmol). The reaction mixture was stirred at rt for 1 h, quenchedwith saturated aqueous NaHCO₃ (6.9 mL) and 20% Na₂SO₃ (6.9 mL), andextracted twice with MTBE (10.35 mL, 86.888 mmol). The organic layerswere combined and washed with brine. After concentration, the residuewas purified by silica gel column chromatography (ethylacetate/n-heptane=1/10 to 1/2) to give the title compound (366 mg, 69%for 2 steps).

(R)-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-((triethylsilyl)oxy)propyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)-2-oxopropyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2-yl)-5-bromohex-5-en-3-ylbenzoate

A solution of(R)-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-((triethylsilyl)oxy)propyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)-2-oxo-3-(phenylsulfonyl)propyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2-yl)-5-bromohex-5-en-3-ylbenzoate (0.366 g, 0.258 mmol) in a mixture of THF (2.9 mL) and methanol(1.8 mL) was cooled to −78° C. and treated with 0.1M SmI₂ in THF (5.55mL, 0.555 mmol). After stirring at −78° C. for 1 h, the cold bath wasremoved, and the mixture was treated with a mixture of potassium sodiumtartrate (1.83 g, 6.48 mmol) and potassium carbonate (1.7 g, 13 mmol) inwater (18.3 mL). The mixture was vigorously stirred at rt for 10 min andextracted twice with MTBE (7.32 mL). The organic layers were combinedand washed with brine. After concentration, the residue was purified bysilica gel column chromatography (ethyl acetate/n-heptane=1/10 to 1/2)to give the title compound (289 mg, 88%). ¹H NMR (400 MHz, CDCl₃) δ 0.15(s, 9H), 0.30 (s, 3H), 0.58 (q, 6H), 0.88 (s, 9H), 0.89 (s, 9H), 0.95(t, 9H), 0.98-1.05 (m, 2H), 1.06 (d, 3H), 1.20-1.72 (m, 7H), 1.72-1.84(m, 3H), 1.84-2.16 (m, 9H), 2.25 (m, 1H), 2.42 (m, 2H), 2.55 (dd, 1H),2.72-2.86 (m, 2H), 2.92 (m, 2H), 3.34 (dd, 1H), 3.52 (s, 3H), 3.44-3.68(m, 6H), 3.75 (m, 2H), 3.85 (m, 2H), 4.04 (m, 1H), 4.19 (dd, 1H), 4.24(m, 1H), 4.39 (m, 1H), 4.59 (m, 1H), 4.67 (m, 1H), 4.78 (s, 1H), 4.84(m, 1H), 5.45 (m, 1H), 5.48 (s, 1H), 5.68 (s, 1H), 7.41 (m, 2H), 7.58(m, 1H), 8.02 (m, 2H).

1-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-2-(((2R,4R,6S)-6-(3-hydroxypropyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-4-methoxytetrahydrofuran-3-yl)-3-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-2-((R)-5-bromo-3-hydroxyhex-5-en-1-yl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-7-yl)propan-2-one

A solution of(R)-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-((triethylsilyl)oxy)propyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)-2-oxopropyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2-yl)-5-bromohex-5-en-3-ylbenzoate (0.285 g, 0.223 mmol) in a mixture of methanol (5.7 mL) and THF(0.29 mL) was treated with 6-10% Mg(OMe)₂ in methanol (1.29 g, 0.893mmol) and stirred at rt for 5 d. Potassium carbonate (0.093 g, 0.67mmol) was added, and stirring was continued at rt for another 1 d. Thereaction was quenched with saturated aqueous NH₄Cl (4.28 mL) and brine(4.28 mL) and extracted three times with MTBE (11.40 mL). The organiclayers were combined, dried over MgSO₄, and concentrated in vacuo togive the title compound (280 mg, 119%).

1-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-((triethylsilyl)oxy)propyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)-3-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-2-((R)-5-bromo-3-hydroxyhex-5-en-1-yl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-7-yl)propan-2-one

A solution of1-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-2-(((2R,4R,6S)-6-(3-hydroxypropyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-4-methoxytetrahydrofuran-3-yl)-3-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-2-((R)-5-bromo-3-hydroxyhex-5-en-1-yl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-7-yl)propan-2-one(0.28 g, 0.265 mmol) in CH₂Cl₂ (5.6 mL) was cooled to −78° C. andtreated with 2,6-lutidine (0.123 mL, 1.06 mmol) and chlorotriethylsilane(0.054 mL, 0.32 mmol). The reaction mixture was stirred at −78° C. for 2h. The reaction was quenched with methanol (0.107 mL, 2.65 mmol) andstirred at −78° C. for 10 min. After removing the cold bath, the mixturewas treated with water (5.6 mL) and warmed to rt. The mixture wasextracted twice with MTBE (11.20 mL). The organic layers were combined,washed with 0.1 N HCl (6.09 mL, 0.609 mmol) and saturated aqueous NaHCO₃(2.80 mL), dried over MgSO₄, and concentrated in vacuo to give the titlecompound (327 mg, 105%).

(R)-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-((triethylsilyl)oxy)propyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)-2-oxopropyl)decahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2(3H)-yl)-5-bromohex-5-en-3-yl4-methylbenzenesulfonate

1-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-((triethylsilyl)oxy)propyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)-3-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-2-((R)-5-bromo-3-hydroxyhex-5-en-1-yl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-7-yl)propan-2-one(0.327 g, 0.279 mmol) was dissolved in CH₂Cl₂ (4.9 mL) and treated withDMAP (0.102 g, 0.837 mmol) and p-TsCl (0.064 g, 0.34 mmol). The mixturewas stirred at rt for 16 h. Additional DMAP (0.020 g, 0.17 mmol) andp-TsCl (0.016 g, 0.084 mmol) were added, and stirring was continued atrt for another 24 h. The reaction mixture was diluted with MTBE (20 mL)and sequentially washed with 0.1 N HCl (8.4 mL×2), saturated aqueousNaHCO₃ (3.3 mL), and brine (3.3 mL). After concentration, the residuewas purified by column chromatography (ethyl acetate/n-heptane=1/10 to2/3) to give the title compound (215 mg, 72% for 3 steps). ¹H NMR (400MHz, CDCl₃) □ 0.03 (2s, 9H), 0.60 (s, 3H), 0.59 (q, 6H), 0.85 (s, 9H),0.87 (s, 9H), 0.94 (t, 9H), 0.96-1.10 (m, 2H), 1.06 (d, 3H), 1.28-1.60(m, 5H), 1.60-1.84 (m, 6H), 1.84-2.16 (m, 8H), 2.24 (m, 1H), 2.42 (m,2H), 2.51 (dd, 1H), 2.64 (dd, 1H), 2.72 (dd, 1H), 2.82 (dd, 1H), 2.90(d, 1H), 3.26 (m, 1H), 3.52 (s, 3H), 3.44-3.68 (m, 6H), 3.75 (m, 2H),3.84 (m, 2H), 4.04 (m, 1H), 4.19 (m, 1H), 4.35 (m, 1H), 4.58 (m, 1H),4.66 (m, 1H), 4.67 (m, 1H), 4.78 (s, 1H), 4.85 (m, 1H), 4.84 (s, 1H),5.35 (m, 1H), 5.58 (s, 1H), 7.35 (d, 2H), 7.80 (d, 2H)

(R)-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-oxopropyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)-2-oxopropyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2-yl)-5-bromohex-5-en-3-yl4-methylbenzenesulfonate

A solution of 2 M oxalic chloride in CH₂Cl₂ (0.810 mL, 1.62 mmol) inCH₂Cl₂ (4.30 mL) was cooled to −78° C. and treated with DMSO (0.230 mL,3.24 mmol). After stirring for 10 min at −78° C., a solution of(R)-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-((triethylsilyl)oxy)propyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)-2-oxopropyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2-yl)-5-bromohex-5-en-3-yl4-methylbenzenesulfonate (0.215 g, 0.162 mmol) in CH₂Cl₂ (2.2 mL) wasadded. The mixture was stirred at −78° C. for 10 min and at −40° C. for1 h. After cooling back to −78° C., the mixture was treated withtriethylamine (1.13 mL, 8.10 mmol) and stirred at −78° C. for 10 min andat 0° C. for 20 min. The resulting mixture was treated with water (4.3mL) and diluted with MTBE (21.5 mL). The organic layer was separated andwashed with brine. After concentration, the residue was purified bysilica gel column chromatography (ethyl acetate/n-heptane=1/10 to 1/1)to give the title compound (166 mg, 85%).

BisTBS Ether

Chromous chloride (0.520 g, 4.23 mmol) was added to a 3-necked flask,which was purged with N₂ for 5 min, and to the flask was added asolution of(R)-N-(2-(4-isopropyl-4,5-dihydrooxazol-2-yl)-6-methylphenyl)methanesulfonamide(1.25 g, 4.23 mmol) in a degassed THF (7.5 mL). The mixture was heatedto 30° C., treated with triethylamine (0.590 mL, 4.23 mmol), and stirredat 33° C. for 1 h. After cooling to 0° C., the mixture was treated withnickel(II) chloride 2,9-dimethyl-1,10-phenanthroline complex (0.023 g,0.069 mmol) and purged with N₂ for 5 min. After removing the ice-bath, asolution of(R)-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-oxopropyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)-2-oxopropyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2-yl)-5-bromohex-5-en-3-yl4-methylbenzenesulfonate (0.083 g, 0.069 mmol) in a degassed THF (4.98mL) was added over 2 h by syringe pump. The mixture was stirred at rtfor another 2 h. After cooling to 0° C., the reaction was quenched withethylenediamine (0.926 mL, 13.7 mmol), while maintaining the internaltemperature below 10° C., and stirred at rt for 10 min. The mixture wastreated with water (9.96 mL) and extracted twice with MTBE (9.96 mL).The organic layers were combined, dried over MgSO₄, and concentrated invacuo.

The residue was dissolved in isopropanol (IPA) (4.98 mL), treated withsilica gel (166 mg), and stirred at rt for 23 h. The precipitate wasfiltered and washed with IPA (3 mL) and heptane (3 mL). The filtrate wasaged in a freezer for 2 d. The resulting precipitate was filtered andwashed with IPA (5 mL). The filtrate was concentrated and purified bysilica gel column chromatography (ethyl acetate/n-heptane=1/10 to 3/2)to give the title compound (33 mg, 50%), the structure of which wasconfirmed by comparison of its ¹H NMR spectrum with that of an authenticsample. ¹H NMR (400 MHz, C₆D₆) δ 0.05 (s, 6H), 0.14 (s, 3H), 0.16 (s,3H), 0.77 (d, 3H), 0.94 (s, 9H), 0.99 (s, 9H), 1.05-1.30 (m, 2H),1.30-1.46 (m, 3H), 1.20-1.72 (m, 2H), 1.50-1.70 (m, 3H), 1.84-2.00 (m,4H), 2.05-2.20 (m, 3H), 2.28-2.40 (m, 4H), 2.50 (m, 2H), 2.60 (m, 2H),2.70 (m, 2H), 2.86 (m, 1H), 3.50 (m, 1H), 3.52-3.72 (m, 4H), 3.58 (s,3H), 3.74-3.84 (m, 2H), 3.95 (m, 1H), 4.00-4.22 (m, 7H), 4.04 (m, 1H),4.38 (m, 1H), 4.56 (bm, 1H), 4.57 (s, 1H), 4.74 (s, 1H), 4.98 (m, 2H).

All compounds were prepared following the same procedures shown abovestarting from (S)-2-bromo-7-((tert-butyldiphenylsilyl)oxy)hept-1-en-4-ylbenzoate.

(S)-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-oxopropyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)-2-oxopropyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2-yl)-5-bromohex-5-en-3-ylbenzoate

The compound was prepared following the same procedures shown above for(3R)-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-((triethylsilyl)oxy)propyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)-2-hydroxy-3-(phenylsulfonyl)propyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2-yl)-5-bromohex-5-en-3-ylbenzoate with the exception that(S)-5-bromo-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(2-oxoethyl)decahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2(3H)-yl)hex-5-en-3-ylbenzoate was used as a starting material.

NHK Macrocyclization

Chromous chloride (0.636 g, 5.18 mmol) was added to a 3-necked flask,which was purged with N₂ for 5 min, and to the flask was added asolution of(S)-N-(2-(4-isopropyl-4,5-dihydrooxazol-2-yl)-6-methylphenyl)methanesulfonamide(1.535 g, 5.18 mmol) in a degassed THF (6.80 mL). The resulting mixturewas heated to 30° C., charged with triethylamine (0.722 mL, 5.18 mmol),and stirred at 33° C. for 1 h. After cooling to 0° C., the mixture wastreated with nickel(II) chloride 2,9-dimethyl-1,10-phenanthrolinecomplex (0.040 g, 0.12 mmol) and purged with N₂ for 5 min. Afterremoving the ice-bath, a solution of(S)-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-oxopropyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)-2-oxopropyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2-yl)-5-bromohex-5-en-3-ylbenzoate (compound 8; 0.136 g, 0.117 mmol) in a degassed THF (6.80 mL)was added over 1.5 h by syringe pump. The mixture was stirred at rt foranother 2 h. The reaction was cooled to 0° C., quenched withethylenediamine (1.045 mL, 15.47 mmol), while maintaining the internaltemperature below 10° C., and stirred at rt for 10 min. The mixture wastreated with water (16.3 mL) and extracted with n-heptane (8.2 mL) andthen twice with MTBE (16.3 mL). The organic layers were combined, driedover MgSO₄, and concentrated in vacuo. The residue was treated withn-heptane (20 mL) and stirred at rt for 20 min. The precipitated ligandwas filtered off and rinsed with heptane (20 mL) and IPA (10 mL). Thefiltrate was aged in a freezer (−20° C.) for 20 h. The precipitate wasfiltered and rinsed with IPA. The filtrate was concentrated and purifiedby silica gel column chromatography (ethyl acetate/n-heptane=1/10 to1/1) to give compound 16 (88 mg, 69%). ¹H NMR (400 MHz, CDCl₃) δ 0.02(s, 9H), 0.6 (s, 3H), 0.86 (s, 18H), 1.10 (m, 4H), 1.42 (m, 3H),1.64-2.00 (m, 8H), 2.06-2.30 (m, 8H), 2.45 (m, 2H), 2.64 (m, 2H), 2.94(m, 2H), 3.11 (m, 1H), 3.19 (m, 1H), 3.36 (s, 3H), 3.48 (m, 1H), 3.56(m, 1H), 3.64-3.90 (m, 5H), 3.80-4.30 (m, 4H), 4.41 (m, 1H), 4.59 (m,1H), 4.68 (m, 1H), 4.79 (m, 1H), 4.92 (s, 1H), 5.06 (s, 1H), 5.28 (s,1H), 5.40 (m, 1H), 7.41 (m, 2H), 7.58 (m, 1H), 8.02 (m, 2H).

Mesylation of NHK Product

A solution of Compound 16 (0.084 g, 0.078 mmol) in THF (2.94 mL) wascooled to 0° C. and treated with triethylamine (0.043 mL, 0.31 mmol) andmethanesulfonyl chloride (0.018 mL, 0.23 mmol). After stirring at 0° C.for 30 min, the reaction was quenched with water (3.36 mL) and extractedthree times with MTBE (5.04 mL). The organic layers were combined, driedover MgSO₄, and concentrated to give compound 17 (88 mg).

Cyclization with KOMe

A solution of compound 17 (0.080 g, 0.069 mmol) in THF (4.0 mL) wascooled to 0° C. and treated with 25% potassium methoxide in methanol(0.068 g, 0.24 mmol). The mixture was slowly warmed to rt over 20 h. Thereaction was quenched with saturated aqueous NH₄Cl (2.4 mL) andextracted three times with MTBE (6.4 mL). The organic layers werecombined and dried over MgSO₄. After concentration, the residue waspurified by silica gel column chromatography (ethylacetate/n-heptane=1/10 to 2/1) to give compound 18 (45 mg, 68% for 2steps). ¹H NMR (400 MHz, C₆D₆) δ 0.05 (s, 6H), 0.14 (s, 3H), 0.16 (s,3H), 0.77 (d, 3H), 0.94 (s, 9H), 0.99 (s, 9H), 1.05-1.30 (m, 2H),1.30-1.46 (m, 3H), 1.20-1.72 (m, 2H), 1.50-1.70 (m, 3H), 1.84-2.00 (m,4H), 2.05-2.20 (m, 3H), 2.28-2.40 (m, 4H), 2.50 (m, 2H), 2.60 (m, 2H),2.70 (m, 2H), 2.86 (m, 1H), 3.50 (m, 1H), 3.52-3.72 (m, 4H), 3.58 (s,3H), 3.74-3.84 (m, 2H), 3.95 (m, 1H), 4.00-4.22 (m, 7H), 4.04 (m, 1H),4.38 (m, 1H), 4.56 (bm, 1H), 4.57 (s, 1H), 4.74 (s, 1H), 4.98 (m, 2H).

Example 8 Preparation of a Compound of Formula (ID) Through C.26-C.27Macrocyclization

(R)-4-((2S,3aS,5R,7aS)-2-(3-hydroxypropyl)-3a-(iodomethyl)hexahydro-2H-furo[3,2-b]pyran-5-yl)-3-methylbut-1-en-2-yltrifluoromethanesulfonate

A solution of3-((2S,3aS,5R,7aS)-3a-(iodomethyl)-5-((R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)but-3-en-1-yl)hexahydro-2H-furo[3,2-b]pyran-2-yl)propylpivalate (6.80 g, 10.9 mmol) in CH₂Cl₂ (68.0 mL) was cooled to −78° C.and treated with 1 M DIBAL in toluene (23.88 mL, 23.88 mmol) over 20min, while maintaining the internal temperature below −70° C. Thereaction mixture was stirred at −78° C. for 30 min. The reaction wasquenched with methanol (4.39 mL), while maintaining the internaltemperature below −60° C. After removing the cold bath, the mixture wastreated with 1 N HCl (109 mL) and MTBE (102 mL) and stirred at ambienttemperature for 20 min. The organic layer was separated, and the aqueouslayer was extracted with MTBE (102 mL). The organic layers werecombined, dried over MgSO₄, and concentrated to give the title compound(8.8 g, contaminated with toluene). ¹H NMR (400 MHz, CDCl₃) δ 1.14 (d,3H), 1.22 (m, 1H), 1.45-1.70 (m, 8H), 1.72-1.90 (m, 2H), 2.42 (m, 1H),2.83 (m, 1H), 3.40 (d, 1H), 3.46 (d, 1H), 3.55 (m, 1H), 3.65 (m, 2H),3.79 (m, 1H), 4.22 (m, 1H), 5.03 (d, 1H), 5.10 (d, 1H).

(R)-4-((2S,3aS,5R,7aS)-3a-(iodomethyl)-2-(3-oxopropyl)hexahydro-2H-furo[3,2-b]pyran-5-yl)-3-methylbut-1-en-2-yltrifluoromethanesulfonate

A solution of(R)-4-((2S,3aS,5R,7aS)-2-(3-hydroxypropyl)-3a-(iodomethyl)hexahydro-2H-furo[3,2-b]pyran-5-yl)-3-methylbut-1-en-2-yltrifluoromethanesulfonate (2.64 g, 4.87 mmol) in CH₂Cl₂ (26.4 mL) wastreated with Dess-Martin periodinane (3.10 g, 7.30 mmol) and stirred atrt for 1 h. The reaction was quenched with saturated aqueous NaHCO₃ (20mL) and 20% Na₂SO₃ (20 mL) and extracted three times with MTBE (20 mL).The organic layers were combined and washed with brine. Afterconcentration, the residue was purified by silica gel columnchromatography (ethyl acetate/n-heptane1=710 to 1/3) to give the titlecompound (970 mg, 56% for 2 steps). ¹H NMR (400 MHz, CDCl₃) δ 1.14 (d,3H), 1.15-1.30 (m, 2H), 1.45-1.70 (m, 5H), 1.72-1.90 (m, 2H), 2.32 (dd,1H), 2.52 (m, 2H), 2.83 (m, 1H), 3.37 (d, 1H), 3.43 (d, 1H), 3.52 (m,1H), 3.72 (m, 1H), 4.19 (m, 1H), 5.01 (d, 1H), 5.09 (d, 1H), 9.76 (s,1H).

(3R)-4-((2S,3aS,5R,7aS)-2-((6S,E)-6-((2S,3R,4S,4aS,6R,8aS)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(2-((triethylsilyl)oxy)ethyl)octahydropyrano[3,2-b]pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-3-hydroxyhex-4-en-1-yl)-3a-(iodomethyl)hexahydro-2H-furo[3,2-b]pyran-5-yl)-3-methylbut-1-en-2-yltrifluoromethanesulfonate

A solution of(((2S,3R,4S,4aS,6R,8aS)-2-((S,E)-1-((tert-butyldimethylsilyl)oxy)-3-iodoallyl)-6-(2-((triethylsilyl)oxy)ethyl)octahydropyrano[3,2-b]pyran-3,4-diyl)bis(oxy))bis(tert-butyldimethylsilane)(1.295 g, 1.51 mmol) in THF (10.20 mL) was cooled to −78° C. and treatedwith 1.6 M n-BuLi in hexane (0.944 mL, 1.51 mmol), while maintaining theinternal temperature below −60° C. After stirring at −78° C. for 15 min,the mixture was treated with a solution of magnesium bromide diethyletherate (0.390 g, 1.51 mmol) in a mixture of THF (6 mL) and toluene (1mL), while maintaining the internal temperature below −60° C., andstirred at −78° C. for 30 min. A solution of(R)-4-((2S,3aS,5R,7aS)-3a-(iodomethyl)-2-(3-oxopropyl)hexahydro-2H-furo[3,2-b]pyran-5-yl)-3-methylbut-1-en-2-yltrifluoromethanesulfonate (0.68 g, 1.258 mmol) in THF (6.80 mL) wasadded, and the resulting mixture was stirred at −78° C. for 3 h andslowly warmed to rt over 14 h. The reaction was quenched with saturatedaqueous NH₄Cl (6.80 mL) and extracted twice with MTBE (0.150 mL). Theorganic layers were combined and washed with brine. After concentration,the residue was purified by silica gel column chromatography (ethylacetate/n-heptane=1/10 to 1/3) to give the title compound (455 mg, 28%).

(6S,E)-6-((2S,3R,4S,4aS,6R,8aS)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(2-((triethylsilyl)oxy)ethyl)octahydropyrano[3,2-b]pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-1-((2S,3aS,5R,7aS)-3a-(iodomethyl)-5-((R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)but-3-en-1-yl)hexahydro-2H-furo[3,2-b]pyran-2-yl)hex-4-en-3-ylbenzoate

A solution of(3R)-4-((2S,3aS,5R,7aS)-2-((6S,E)-6-((2S,3R,4S,4aS,6R,8aS)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(2-((triethylsilyl)oxy)ethyl)octahydropyrano[3,2-b]pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-3-hydroxyhex-4-en-1-yl)-3a-(iodomethyl)hexahydro-2H-furo[3,2-b]pyran-5-yl)-3-methylbut-1-en-2-yltrifluoromethanesulfonate (0.455 g, 0.358 mmol) in CH₂Cl₂ (4.55 mL) wastreated with benzoyl chloride (0.083 mL, 0.72 mmol), triethylamine (0.15mL, 1.1 mmol) and DMAP (4.4 mg, 0.036 mmol). The mixture was stirred atambient temperature for 40 h. The reaction was quenched with water (4.6mL) and extracted twice with MTBE (9.1 mL). The organic layers werecombined and washed with brine. After concentration, the residue waspurified by silica gel column chromatography (ethylacetate/n-heptane=1/10 to 1/5) to give the title compound (316 mg, 64%).¹H NMR (400 MHz, CDCl₃) δ −0.08-0.12 (multiple s, 18H), 0.55 (m, 6H),0.81 (2s, 9H), 0.85-1.00 (m, 27H), 1.05-1.30 (m, 2H), 1.12 (d, 3H),1.40-1.90 (m, 16H), 2.29 (m, 1H), 2.80 (m, 2H), 3.30-3.45 (m, 3H), 3.53(m, 2H), 3.65 (m, 1H), 3.72 (m, 1H), 3.83 (m, 2H), 4.08 (m, 1H), 4.19(m, 1H), 4.98 (m, 1H), 5.02 (m, 1H), 5.07 (m, 1H), 5.60 (m, 1H), 5.77(m, 1H), 6.05 (m, 1H), 7.40 (m, 2H), 7.52 (m, 1H), 8.02 (m, 2H).

(6S,E)-6-((2S,3R,4S,4aS,6R,8aS)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(2-oxoethyl)octahydropyrano[3,2-b]pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-1-((2S,3aS,5R,7aS)-3a-(iodomethyl)-5-((R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)but-3-en-1-yl)hexahydro-2H-furo[3,2-b]pyran-2-yl)hex-4-en-3-ylbenzoate

A solution of oxalyl chloride (0.141 mL, 1.61 mmol) in CH₂Cl₂ (6.32 mL)was cooled to −78° C. and treated with DMSO (0.228 mL, 3.22 mmol). Afterstirring for 10 min at −78° C., the mixture was treated with a solutionof(6S,E)-6-((2S,3R,4S,4aS,6R,8aS)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(2-((triethylsilyl)oxy)ethyl)octahydropyrano[3,2-b]pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-1-((2S,3aS,5R,7aS)-3a-(iodomethyl)-5-((R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)but-3-en-1-yl)hexahydro-2H-furo[3,2-b]pyran-2-yl)hex-4-en-3-ylbenzoate (0.316 g, 0.230 mmol) in CH₂Cl₂ (3.8 mL). The mixture wasstirred at −78° C. for 20 min and at −40° C. for 1 h. After cooling to−78° C., the mixture was treated with triethylamine (1.12 mL, 8.04 mmol)and stirred at −78° C. for 10 min and at 0° C. for 20 min. The reactionmixture was treated with water (6.3 mL) and diluted with MTBE (6.32 mL).The organic layer was separated and washed with brine. Afterconcentration, the residue was purified by silica gel columnchromatography (ethyl acetate/n-heptane=1/10 to 1/2) to give the titlecompound (284 mg).

(6S,E)-6-((2S,3R,4S,4aS,6R,8aS)-6-(3-((2S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(2-((triethylsilyl)oxy)ethyl)tetrahydrofuran-3-yl)-2-hydroxy-3-(phenylsulfonyl)propyl)-3,4-bis((tert-butyldimethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-1-((2S,3aS,5R,7aS)-3a-(iodomethyl)-5-((R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)but-3-en-1-yl)hexahydro-2H-furo[3,2-b]pyran-2-yl)hex-4-en-3-ylbenzoate

A solution of(S)-5-(((2R,3R,4S,5S)-3-methoxy-4-((phenylsulfonyl)methyl)-5-(2-((triethylsilyl)oxy)ethyl)tetrahydrofuran-2-yl)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane(0.214 g, 0.298 mmol) in THF (3 mL) was cooled to −5° C. The mixture wastreated with 1.6 M n-BuLi in hexane (0.186 mL, 0.298 mmol) and stirredat −5° C. for 20 min. After cooling to −78° C., the mixture was treatedwith a solution of(6S,E)-6-((2S,3R,4S,4aS,6R,8aS)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(2-oxoethyl)octahydropyrano[3,2-b]pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-1-((2S,3aS,5R,7aS)-3a-(iodomethyl)-5-((R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)but-3-en-1-yl)hexahydro-2H-furo[3,2-b]pyran-2-yl)hex-4-en-3-ylbenzoate (0.150 g, 0.119 mmol) in n-heptane (4.2 mL). The mixture wasstirred at −78° C. for 4 h. The reaction was quenched with saturatedaqueous NH₄Cl (7.5 mL) and extracted twice with MTBE (15 mL). Theorganic layers were combined and washed with brine. After concentration,the residue was purified by silica gel column chromatography (ethylacetate/n-heptane=1/20 to 1/2) to give the title compound (177 mg, 75%).

(6S,E)-6-((2S,3R,4S,4aS,6R,8aS)-6-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(2-((triethylsilyl)oxy)ethyl)tetrahydrofuran-3-yl)-2-oxo-3-(phenylsulfonyl)propyl)-3,4-bis((tert-butyldimethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-1-((2S,3aS,5R,7aS)-3a-(iodomethyl)-5-((R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)but-3-en-1-yl)hexahydro-2H-furo[3,2-b]pyran-2-yl)hex-4-en-3-ylbenzoate

A solution of(6S,E)-6-((2S,3R,4S,4aS,6R,8aS)-6-(3-((2S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(2-((triethylsilyl)oxy)ethyl)tetrahydrofuran-3-yl)-2-hydroxy-3-(phenylsulfonyl)propyl)-3,4-bis((tert-butyldimethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-1-((2S,3aS,5R,7aS)-3a-(iodomethyl)-5-((R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)but-3-en-1-yl)hexahydro-2H-furo[3,2-b]pyran-2-yl)hex-4-en-3-ylbenzoate (0.177 g, 0.09 mmol) in CH₂Cl₂ (3.54 mL) was treated withsodium bicarbonate (0.011 g, 0.13 mmol) and Dess-Martin periodinane(0.057 g, 0.13 mmol) and stirred at rt for 1 h. Additional Dess-Martinperiodinane (0.019 g, 0.045 mmol) was added, and stirring was continuedat rt for another 1 h. The reaction was quenched with saturated aqueousNaHCO₃ (3.5 mL) and 20% Na₂SO₃ (3.5 mL) and extracted twice with MTBE(3.5 mL). The organic layers were combined and washed with brine. Afterconcentration, the residue was purified by silica gel columnchromatography (ethyl acetate/n-heptane=1/10 to 1/3) to give the titlecompound (170 mg, 96%).

(6S,E)-6-((2S,3R,4S,4aS,6R,8aS)-6-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(2-((triethylsilyl)oxy)ethyl)tetrahydrofuran-3-yl)-2-oxopropyl)-3,4-bis((tert-butyldimethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-1-((2S,3aS,5R,7aS)-3a-(iodomethyl)-5-((R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)but-3-en-1-yl)hexahydro-2H-furo[3,2-b]pyran-2-yl)hex-4-en-3-ylbenzoate

A solution of(6S,E)-6-((2S,3R,4S,4aS,6R,8aS)-6-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(2-((triethylsilyl)oxy)ethyl)tetrahydrofuran-3-yl)-2-oxo-3-(phenylsulfonyl)propyl)-3,4-bis((tert-butyldimethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-1-((2S,3aS,5R,7aS)-3a-(iodomethyl)-5-((R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)but-3-en-1-yl)hexahydro-2H-furo[3,2-b]pyran-2-yl)hex-4-en-3-ylbenzoate (0.17 g, 0.086 mmol) in a mixture of THF (1.4 mL) and methanol(0.85 mL) was cooled to −78° C. and treated with 0.1 M SmI₂ in THF (1.29mL, 0.129 mmol). After stirring at −78° C. for 1 h, additional 0.1 MSmI₂ in THF (0.86 mL, 0.086 mmol) was added, and stirring was continuedat −78° C. for another 2 h. The reaction was quenched with a mixture ofRochelle's Salt (510 mg, 1.807 mmol), potassium carbonate (509 mg, 3.69mmol), and water (5.1 mL) and extracted twice with MTBE (8.5 mL). Theorganic layers were combined and dried over MgSO₄ to give the titlecompound (127 mg, 80%).

(6S,E)-6-((2S,3R,4S,4aS,6R,8aS)-6-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(2-oxoethyl)tetrahydrofuran-3-yl)-2-oxopropyl)-3,4-bis((tert-butyldimethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-1-((2S,3aS,5R,7aS)-3a-(iodomethyl)-5-((R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)but-3-en-1-yl)hexahydro-2H-furo[3,2-b]pyran-2-yl)hex-4-en-3-ylbenzoate

A solution of oxalyl chloride (0.061 mL, 0.69 mmol) in CH₂Cl₂ (2.54 mL)was cooled to −78° C. and treated with DMSO (0.098 mL, 1.4 mmol). Afterstirring at −78° C. for 10 min, a solution of(6S,E)-6-((2S,3R,4S,4aS,6R,8aS)-6-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(2-((triethylsilyl)oxy)ethyl)tetrahydrofuran-3-yl)-2-oxopropyl)-3,4-bis((tert-butyldimethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-1-((2S,3aS,5R,7aS)-3a-(iodomethyl)-5-((R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)but-3-en-1-yl)hexahydro-2H-furo[3,2-b]pyran-2-yl)hex-4-en-3-yl benzoate (0.127 g,0.069 mmol) in CH₂Cl₂ (2.5 mL) was added. The resulting solution wasstirred at −78° C. for 10 min and at −40° C. for 1 h. After cooling to−78° C., the mixture was treated with triethylamine (0.5 mL, 3.6 mmol)and stirred at −78° C. for 10 min and at 0° C. for 20 min. The mixturewas treated with water (5 mL) and extracted twice with MTBE (10 mL). Theorganic layers were combined and washed with brine. After concentration,the residue was purified by silica gel column chromatography (ethylacetate/n-heptane=1/10 to 1/5) to give the title compound (86 mg, 72%).

NHK Macrocyclization

(S)-N-(2-(4-isopropyl-4,5-dihydrooxazol-2-yl)-6-methylphenyl)methanesulfonamide (0.829 g, 2.797 mmol) was dissolved in a degassedacetonitrile (7.12 mL) and treated with chromous chloride (0.346 g, 2.82mmol). After purging with nitrogen gas for 5 min, the mixture was heatedto 30° C. and treated with Et₃N (0.39 mL, 2.8 mmol). The mixture wasstirred at 34° C. for 1 h. After cooling to 0° C., the mixture wastreated with nickel chloride (6.7 mg, 0.052 mmol) and purged withnitrogen gas for 5 min. After removing the ice-bath, the mixture wastreated with a solution of(6S,E)-6-((2S,3R,4S,4aS,6R,8aS)-6-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(2-oxoethyl)tetrahydrofuran-3-yl)-2-oxopropyl)-3,4-bis((tert-butyldimethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-1-((2S,3aS,5R,7aS)-3a-(iodomethyl)-5-((R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)but-3-en-1-yl)hexahydro-2H-furo[3,2-b]pyran-2-yl)hex-4-en-3-yl benzoate(0.089 g, 0.052 mmol) in a mixture of THF (3.1 mL) and acetonitrile (1.4mL) over 40 min via syringe pump. The mixture was stirred at 20° C. foranother 2 h. The mixture was diluted with n-heptane (8.90 mL), filteredto remove insoluble residue, and washed with n-heptane (8.90 mL). Theheptane layer was separated, and the acetonitrile layer was extractedwith n-heptane (8.9 mL). The heptane layers were combined and washedtwice with acetonitrile (8.90 mL). After concentration, the residue waspurified by silica gel column chromatography (ethylacetate/n-heptane=1/10 to 1/2) to give the compound 19 (18 mg and 11 mgof two products epimeric at C.14, total 36%). Mass [M+NH₄]=1587.0 and1586.9, respectively for two products (calc. 1586.8).

Acetylation

A solution of compound 19 (0.029 g, 0.018 mmol) in CH₂Cl₂ (3 mL) wastreated with acetic anhydride (0.012 mL, 0.13 mmol), triethylamine(0.026 mL, 0.19 mmol) and DMAP (0.226 mg, 1.85 μmol). After stirring for1 h at rt, additional triethylamine (0.026 mL, 0.19 mmol), aceticanhydride (0.012 mL, 0.13 mmol), and DMAP (0.226 mg, 1.85 μmol) wereadded, and stirring was continued at rt for another 3 h. The reactionwas quenched with water and extracted twice with MTBE. The organiclayers were combined and dried over MgSO₄. After concentration, theresidue was filtered through silica gel pad, and the filtrate wasconcentrated in vacuo to give compound 20 (30 mg).

Vasella Fragmentation

A solution of compound 20 (0.030 g, 0.019 mmol) in THF (1.2 mL) wastreated with water (0.3 mL), zinc dust (0.036 g, 0.56 mmol), and aceticacid (0.021 mL, 0.37 mmol). The mixture was stirred at rt for 2 h.Additional zinc dust (0.036 g, 0.56 mmol) and acetic acid (0.021 mL,0.37 mmol) were added, and stirring was continued at rt for 15 h. Themixture was diluted with MTBE (30 mL) and filtered through a Celite® padto remove insoluble solid. The filtrate was washed twice with saturatedaqueous NaHCO₃ (5 mL), dried over MgSO₄, and concentrated in vacuo togive compound 21 (27 mg).

Mesylation

A solution of compound 21 (0.027 g, 0.018 mmol) in THF (2 mL) was cooledto 0° C. and treated with MsCl (5.7 μL, 0.073 mmol) and triethylamine(0.020 mL, 0.15 mmol). The mixture was stirred at 0° C. for 1 h. Thereaction was quenched with water (4 mL) and extracted twice with MTBE (8mL). The organic layers were combined, dried over MgSO₄, andconcentrated in vacuo to give compound 22 (27 mg).

Cyclization with KOMe

A solution of compound 23 (0.027 g, 0.017 mmol) in THF (3 mL) was cooledto 0° C. and treated with 25% potassium methoxide in methanol (0.025 mL,0.086 mmol). The mixture was stirred at 0° C. for 3 h and slowly warmedto 15° C. over 14 h. The reaction was quenched with saturated aqueousNH₄Cl (2.70 mL) and extracted with MTBE (8.10 mL). The organic layer wasseparated, dried over MgSO₄, and concentrated in vacuo to give compound24 (23 mg).

Oxidation to a Conjugate Ketone

A solution of compound 24 (0.023 g, 0.017 mmol) in CH₂Cl₂ (2 mL) wastreated with Dess-Martin periodinane (0.015 g, 0.035 mmol) and stirredat rt for 30 min. The reaction was quenched with saturated aqueousNaHCO₃ (2 mL) and 20% Na₂SO₃ (2 mL) and extracted with MTBE (2 mL). Theorganic layer was dried over MgSO₄. After concentration, the residue waspurified by silica gel column chromatography (ethylacetate/n-heptane=1/10 to 1/5) to give compound 25 (1 mg). The structurewas confirmed by comparison of the ¹H NMR spectrum with that of anauthentic sample. ¹H NMR (400 MHz, C₆D₆) δ −0.08 (s, 3H), 0.02 (s, 12H),0.03 (s, 3H), 0.04 (s, 3H), 0.11 (s, 3H), 0.13 (s, 3H), 0.18 (s, 3H),0.85 (s, 27H), 0.92 (s, 9H), 0.95 (s, 9H), 1.01 (m, 1H), 1.05 (d, 3H),1.20-1.45 (m, 4H), 1.53 (m, 3H), 1.60-1.85 (m, 7H), 1.92 (m, 2H), 2.03(m, 1H), 2.25 (m, 2H), 2.48 (m, 2H), 2.60-2.78 (m, 4H), 2.84 (dd, 1H),2.93 (dd, 1H), 3.29 (s, 3H), 3.39 (m, 2H), 3.48 (m, 1H), 3.53 (m, 2H),3.66 (m, 1H), 3.77 (m, 1H), 3.70-3.80 (m, 4H), 4.01 (d, 1H), 4.05 (s,2H), 4.22 (m, 1H), 4.75 (s, 1H), 4.82 (s, 1H), 4.88 (s, 1H), 4.98 (s,1H), 4.99 (m, 1H), 6.33 (d, 1H), 7.25 (dd, 1H).

Example 9 Preparation of a Compound of Formula (ID) Through a C.0-C.1Macrocyclization

(S)-3-((2R,3R,4S,5S)-5-(2,2-dimethoxyethyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1,2-diylbis(4-nitrobenzoate)

A solution of(S)-3-((2R,3R,4S,5S)-5-(2,2-dimethoxyethyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1,2-diol(1.90 g, 4.54 mmol) was dissolved in CH₂Cl₂ (19 mL) and treated withpyridine (2.203 mL, 27.24 mmol) and 4-nitrobenzoyl chloride (2.53 g,13.6 mmol). The mixture was stirred at rt for 20 h and at 40° C. for 20h. Additional 4-nitrobenzoyl chloride (0.842 g, 4.54 mmol) and pyridine(0.734 mL, 9.08 mmol) were added, and stirring was continued at 40° C.for another 1 d. The reaction was quenched with water (25 mL), filteredto remove insoluble solid, and extracted twice with MTBE (25 mL). Theorganic layers were combined, washed with 1 N HCl (20 mL) and withsaturated aqueous NaHCO₃ (15 mL), and dried over MgSO₄. Afterconcentration, the residue was purified by silica gel columnchromatography (ethyl acetate/n-heptane=1/10 to 1/1) to give the titlecompound (2.05 g, 77% for 2 steps). ¹H NMR (400 MHz, CDCl₃) δ 1.85 (t,2H), 2.19 (m, 1H), 2.30 (m, 1H), 2.55 (m, 1H), 3.02 (dd, 1H), 3.09 (dd,1H), 3.19 (s, 3H), 3.21 (s, 3H), 3.41 (s, 3H), 3.58 (q, 1H), 3.88 (m,1H), 3.96 (m, 1H), 4.32 (m, 1H), 4.62 (m, 2H), 5.69 (m, 1H), 7.57 (m,2H), 7.66 (m, 1H), 7.89 (m, 2H), 8.13 (d, 2H), 8.18 (d, 2H), 8.25 (m,4H).

Triethyl(((S)-5-methyl-1-((2S,5S)-3-methylene-5-(3-((triethylsilyl)oxy)propyl)tetrahydrofuran-2-yl)hepta-5,6-dien-3-yl)oxy)silane

A mixture of Pd₂(dba)₃ (5.7 mg, 6.2 μmol) and(S)-(−)-(diphenylphosphino)-2′-methoxy-1,1′-binaphthyl (0.012 g, 0.025mmol) was purged with nitrogen for 5 min, treated with n-heptane (1 mL),and stirred at rt for 10 min. After addition of Hünig's base (0.11 mL,0.62 mmol) and a solution of(3R,5R)-3-methyl-7-((2S,5S)-3-methylene-5-(3-((triethylsilyl)oxy)propyl)tetrahydrofuran-2-yl)-5-((triethylsilyl)oxy)hept-1-en-2-yltrifluoromethanesulfonate (0.20 g, 0.31 mmol) in n-heptane (2 mL), themixture was stirred at rt for 20 h, at 35° C. for 2 d, and at 50° C. for1 d. The mixture was cooled to rt, filtered through a Celite® pad toremove the catalyst, and the pad was rinsed with n-heptane. Thecolorless filtrate was concentrated in vacuo to give the title compound(a 1:1 mixture of SM and the allene).

3-((2S,5S)-5-((R)-3-hydroxy-5-methylhepta-5,6-dien-1-yl)-4-methylenetetrahydrofuran-2-yl)propylpivalate

3-((2S,5S)-5-((3R,5R)-3-hydroxy-5-methyl-6-(((trifluoromethyl)sulfonyl)oxy)hept-6-en-1-yl)-4-methylenetetrahydrofuran-2-yl)propylpivalate (90.0 g, 180 mmol) was dissolved in 1,2-dichloroethane (900 mL)and treated with 1-methylimidazole (25.8 mL, 323.632 mmol). The mixturewas stirred at 85° C. for 5 h. After cooling to rt, the mixture wasdiluted with MTBE (1.8 L), sequentially washed with 1.0 M HCl in water(500 mL), water (200 mL), saturated aqueous sodium bicarbonate (150 mL),and brine (150 mL), and dried over Na₂SO₄. After concentration, theresidue was purified by column chromatography (ethylacetate/n-heptane=3/7) to give a mixture of the allene and acetylene.The mixture was further purified by prep. HPLC to give the titlecompound (20 g, 31%). ¹H NMR (400 MHz, CDCl₃) δ 1.10 (s, 9H), 1.40-1.80(m, 8H), 1.72 (s, 3H), 2.10 (m, 2H), 2.27 (dd, 1H), 2.46 (bs, 1H), 2.70(dd, 1H), 3.80 (m, 1H), 4.08 (m, 3H), 4.39 (bm, 1H), 4.66 (m, 2H), 4.87(s, 1H), 5.00 (s, 1H).

(S)-5-methyl-1-((2S,5S)-3-methylene-5-(3-(pivaloyloxy)propyl)tetrahydrofuran-2-yl)hepta-5,6-dien-3-yl4-nitrobenzoate

3-((2S,5S)-5-((R)-3-hydroxy-5-methylhepta-5,6-dien-1-yl)-4-methylenetetrahydrofuran-2-yl)propylpivalate (6.94 g, 19.8 mmol) was dissolved in toluene (35.4 mL) andtreated with 4-nitrobenzoic acid (4.30 g, 25.7 mmol) andtriphenylphosphine (6.75 g, 25.7 mmol). After cooling to 0° C., themixture was charged with DIAD (4.62 mL, 23.7 mmol) and stirred at 0° C.for 2.5 h. The mixture was diluted with MTBE (156 mL) and washed withsaturated aqueous NaHCO₃ (39.0 mL). After concentration, the residue waspurified by silica gel column chromatography (ethylacetate/n-heptane=1/9) to give the title compound (9.9 g, 100%). ¹H NMR(400 MHz, CDCl₃) δ 1.19 (s, 9H), 1.49 (m, 1H), 1.53-1.80 (m, 5H), 1.73(s, 3H), 1.88 (m, 2H), 2.28 (m, 2H), 2.41 (m, 1H), 2.68 (m, 1H), 4.02(m, 1H), 4.08 (m, 2H), 4.40 (m, 1H), 4.45 (m, 1H), 4.52 (m, 1H), 4.81(s, 1H), 4.99 (s, 1H), 5.34 (m, 1H), 8.20 (m, 2H), 8.30 (m, 2H).

3-((2S,5S)-5-((S)-3-hydroxy-5-methylhepta-5,6-dien-1-yl)-4-methylenetetrahydrofuran-2-yl)propylpivalate

(S)-5-methyl-1-((2S,5S)-3-methylene-5-(3-(pivaloyloxy)propyl)tetrahydrofuran-2-yl)hepta-5,6-dien-3-yl4-nitrobenzoate (9.90 g, 19.8 mmol) was dissolved in a mixture of THF(100 mL) and water (50 mL) and treated with lithium hydroxidemonohydrate (2.50 g, 59.4 mmol). The mixture was stirred at rt for 16 h.The reaction mixture was diluted with brine (118 mL) and extracted withMTBE (470 mL). The organic layer was concentrated and purified by silicagel column chromatography (ethyl acetate/n-heptane=15/85) to give thetitle compound (5.55 g, 80%). ¹H NMR (400 MHz, CDCl₃) δ 1.20 (s, 9H),1.40-1.80 (m, 9H), 1.65 (s, 3H), 2.10 (m, 2H), 2.25 (dd, 1H), 2.68 (dd,1H), 3.79 (m, 1H), 4.05 (m, 2H), 4.40 (m, 1H), 4.62 (m, 2H), 4.85 (s,1H), 5.00 (s, 1H).

(S)-3-((2R,3R,4S,5S)-3-methoxy-5-(((2R,6S)-3-(2-methoxyacetoxy)methyl-4-methyl6-(2-((2S5S)-3-methylene-5-(3-(pivalovloxy)propyl)tetrahydrofuran-2yl-)ethyl)-3,6-dihydro-2H-pyran-2-yl)methyl)-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1,2-diyl bis(4-nitrobenzoate)

A mixture of3-((2S,5S)-5-((S)-3-hydroxy-5-methylhepta-5,6-dien-1-yl)-4-methylenetetrahydrofuran-2-yl)propylpivalate (0.200 g, 0.571 mmol) and(S)-3-((2R,3R,4S,5S)-5-(2,2-dimethoxyethyl)-3-methoxy-4-((phenylsulfony)methyl)tetrahydrofuran-2-yl)propane-1,2-diyl bis(4-nitrobenzoate) (0.573 g, 0.799 mmol) wasdissolved in CH₂Cl₂ (8.0 mL) and cooled to −30 ° C. The mixture wassequentially treated with methoxyacetic acid (0.657 mL, 8.56 mmol) andthen BF₃-OEt₂(0.217 mL, 1.71 mmol) and stirred between −30 ° C. and −20° C. for 7 h. The reaction was quenched with saturated aqueous NaHCO₃(14.4 mL) and extracted twice with MTBE (10 mL). The organic layers werecombined and washed with brine. After concentration, the residue waspurified by silica gel column chromatography (ethylacetate/n-heptane=1/10 to 2/3) to give the title compound (518mg, 83%).¹H NMR (400 MHz, CDCl₃) δ 1.18 (s, 9H), 1.40-1.74 (m, 8H), 1.70 (s, 3H),1.76-1.96 (m, 4H), 2.16-2.34 (m, 3H), 2.60-2.70 (m, 2H), 3.00 (dd, 1H),3.16 (dd, 1H), 3.34 (m, 1H), 3.42 (s, 3H), 3.45 (s, 3H), 3.61 (m, 1H),3.82 (m, 1H), 3.94-3.46 (m, 7H), 4.26 (m, 1H), 4.52 (d, 1H), 4.58-4.69(m, 3H), 4.73 (s, 1H), 4.92 (s, 1H), 5.66 (m, 1H), 7.58 (m, 2H), 7.62(m, 1H), 7.90 (m, 2H), 8.1-8.3 (m, 8H).

(S)-3-((2R,3R,4S,5S)-3-methoxy-5-(((2R,4R,6S)-4-methyl-3-methylene-6-(2-((2S,5S)-3-methylene-5-(3-(pivaloyloxy)propyl)tetrahydrofuran-2-yl)ethyl)tetrahydro-2H-pyran-2-yl)methyl)-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1,2-diylbis(4-nitrobenzoate)

A mixture of Pd(Ph₃P)₄ (0.024 g, 0.021 mmol) and triphenylphosphine(0.022 g, 0.084 mmol) in THF (2.3 mL) (in a vial with a cap) was heatedto 60 ° C. and stirred for 5 min. The mixture was treated with a mixtureof(S)-3-((2R,3R,4S,5S)-3-methoxy-5-(((2R,6S)-3-(2-methoxyacetoxy)methyl-4-methyl-6-(2-((2S,5S)-3-methylene-5-(3-(pivaloyloxy)propyl)tetrahydrofuran-2-yl)ethyl)-3,6-dihydro-2H-pyran-2-yl)methyl)-4-((phenylsulfony)methyl)tetrahydrofuran-2-yl)propane-1,2-diyl bis(4-nitrobenzoate) (0.230 g,0.21 mmol), formic acid (0.040 mL, 1.1mmol) and triethylamine (0.147 mL,1.05 mmol) in THF (3.4 mL). The mixture was stirred at 60 ° C. (bath)for 46 h. After cooling to rt, the mixture was treated with water (10.5mL) and extracted twice with MTBE (10.5mL). The organic layers werecombined and washed with brine (10 mL). After concentration, the residuewas purified by silica gel column chromatography (ethylacetate/n-heptane=1/10 to 1/2) to give the title compound (148 mg, 70%).¹H NMR (400 MHz, CDCl₃ ) δ 1.06 (d, 3H), 1.18 (s, 9H), 1.24-1.68 (m,8H), 1.68-1.80 (m, 2H), 1.86 (m, 1H), 2.04-2.28 (m, 4H), 2.56 (m, 1H),2.58-2.68 (m, 2H), 3.05 (m, 2H), 3.36 (m, 1H), 3.46 (s, 3H), 3.58 (dd,1H), 3.73 (m, 1H), 3.85 (m, 1H), 3.95 (m, 1H), 4.01 (m, 1H), 4.06 (m,2H), 4.23 (m, 1H), 4.60-4.72 (m, 3H), 4.78 (s, 2H), 4.92 (s, 1H), 5.72(m, 1H), 7.62 (m, 2H), 7.70 (m, 1H), 7.97 (m, 2H), 8.1-8,3 (m, 8H).

3-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-dihydroxypropyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)propylpivalate

A solution of(S)-3-((2R,3R,4S,5S)-3-methoxy-5-(((2R,4R,6S)-4-methyl-3-methylene-6-(2-((2S,5S)-3-methylene-5-(3-(pivaloyloxy)propyl)tetrahydrofuran-2-yl)ethyl)tetrahydro-2H-pyran-2-yl)methyl)-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1,2-diylbis(4-nitrobenzoate) (1.90 g, 1.89 mmol) in a mixture of THF (1.9 mL)and methanol (38 mL) was treated with 6-10% Mg(OMe)₂ in methanol (2.07mL, 1.13 mmol). The mixture was stirred at rt for 2 h. The reaction wasquenched with saturated aqueous NH₄Cl (19 mL), concentrated to removemethanol, and extracted three times with ethyl acetate (19 mL). Theorganic layers were combined and dried over MgSO₄. After concentration,the residue was purified by column chromatography (ethylacetate/n-heptane=1/10 to 2/1) to give the title compound (934 mg, 70%).¹H NMR (400 MHz, CDCl₃) δ 1.08 (d, 3H), 1.20 (s, 9H), 1.34-1.84 (m,11H), 1.90-2.06 (m, 2H), 2.14-2.26 (m, 3H), 2.58-2.68 (m, 2H), 3.04-3.16(m, 2H), 3.41 (m, 1H), 3.46 (s, 3H), 3.56 (dd, 1H), 3.60 (m, 1H), 3.66(dd, 1H), 3.83 (m, 1H), 3.92 (s, 2H), 3.92-4.00 (m, 2H), 4.07 (m, 2H),4.26 (bm, 1H), 4.68 (d, 1H), 4.80 (d, 1H), 4.85 (s, 1H), 4.92 (s, 1H),7.62 (m, 2H), 7.70 (m, 1H), 7.99 (m, 2H).

3-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)propylpivalate

A solution of3-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-dihydroxypropyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)propylpivalate (0.040 g, 0.057 mmol) in DMF (1 mL) was treated with imidazole(0.019 g, 0.28 mmol) and TBSCl (0.026 g, 0.17 mmol), and stirred at rtfor 3 h. Additional TBSCl (0.026 g, 0.17 mmol) and imidazole (0.019 g,0.28 mmol) were added, and stirring was continued at rt for 3 d. Thereaction was quenched with water (4 mL) and diluted with MTBE (5 mL).The organic layer was separated, washed twice with water (4 mL), anddried over MgSO₄ to give the title compound (40 mg).

3-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)propan-1-ol

A solution of3-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)propylpivalate (0.040 g, 0.043 mmol) in toluene (1.5 mL) was cooled to −78° C.and treated with 1.5 M DIBAL in toluene (0.114 mL, 0.171 mmol). Themixture was stirred at −78° C. for 30 min. Additional 1.5 M DIBAL intoluene (0.057 mL, 0.086 mmol) was added and stirring was continued at−78° C. for another 1 h. The reaction was quenched with 1 N HCl (1 mL)and MTBE (10 mL) and stirred at rt for 1 h. The organic layer wasseparated and sequentially washed with water (5 mL), saturated aqueousNaHCO₃ (5 mL), and brine (3 mL). After concentration, the residue waspurified by silica gel column chromatography (ethylacetate/n-heptane=1/10 to 2/3) to give the title compound (13 mg, 60%for 3 steps). ¹H NMR (400 MHz, CDCl₃) 0.02 (s, 6H), 0.04 (s, 6H), 0.88(s, 18H), 1.02 (d, 3H), 1.34-1.48 (m, 2H), 1.48-1.70 (m, 6H), 1.76 (m,1H), 1.80-1.94 (m, 3H), 2.02 (m, 1H), 2.14-2.28 (m, 3H), 2.56 (m, 1H),2.64 (m, 1H), 3.20 (m, 2H), 3.40 (m, 1H), 3.43 (s, 3H), 3.48 (dd, 1H),3.65-3.72 (m, 5H), 3.76-3.86 (m, 3H), 3.98 (m, 1H), 4.30 (m, 1H), 4.68(s, 1H), 4.78 (s, 1H), 4.86 (s, 1H), 4.92 (s, 1H), 7.60 (m, 2H), 7.70(m, 1H), 8.21 (m, 2H).

3-((2S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)propan-1-al

3-((2S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)propan-1-ol26 (5.72 g, 6.721 mmol) was dissolved in DCM (43.3 mL, 673.711 mmol) andwater (0.036 mL, 2.016 mmol) was added. Dess-Martin Periodinane (DMP)(3.60 g, 8.488 mmol) was added in portions over 4 minutes, whilemaintaining the temperature below 25° C., and the reaction was monitoredby TLC (MTBE and silica gel). Additional DMP (2.550 g, 5.012 mmol) wasadded, and the reaction was stirred until compound 26 was consumed.Saturated aqueous sodium bicarbonate (50 mL) was added followed by 10%aqueous sodium thiosulfate (50 mL). The mixture was partitioned and theaqueous layer extracted twice with dichloromethane (DCM). The combinedDCM extracts were washed with water, and the solution was dried oversodium sulfate and concentrated to provide 27 (5.63 g, 99% yield) as anorange oil that was used as is in the next step.

Methyl2-((2R,4aS,6S,7R,8S,8aS)-6-((1S,E)-6-((2S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)-1-((tert-butyldimethylsilyl)oxy)-4-hydroxyhex-2-en-1-yl)-7,8-bis((tert-butyldimethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)acetate

(S)-N-(2-(4-isopropyl-4,5-dihydrooxazol-2-yl)-6-methylphenyl)methanesulfonamide(3.84 g, 12.94 mmol) was added to a three-neck flask fitted with 3-waystopcock, septum, and solid addition pistol. Chromium(II) chloride (1.59g, 12.94 mmol) was added to the solid addition pistol, and the apparatuswas purged with nitrogen (3×vacuum/N₂-back-flush through the 3-waystopcock). Tetrahydrofuran (17.58 mL) was added. CrCl₂ was added inportions to the vigorously stirred solution. The resulting suspensionwas warmed to 30° C., and TEA (1.85 mL, 12.94 mmol) was added. Thesolution was stirred for 60 minutes before cooling to 0° C.[(2,9-dimethyl-1,10-phenanthroline)dichloronickel(II)] complex (0.224 g,0.663 mmol) in tetrahydrofuran (2.5 mL) was added followed by a mixtureof3-((2S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)propanal27 (2.198 g, 2.588 mmol) and methyl2-((2R,4aS,6S,7R,8S,8aS)-7,8-bis((tert-butyldimethylsilyl)oxy)-6-((S,E)-1-((tert-butyldimethylsilyl)oxy)-3-iodoallyl)octahydropyrano[3,2-b]pyran-2-yl)acetate(2.394 g, 3.106 mmol) in THF (4.4 mL) was added. The reaction was warmedto RT and monitored by TLC and HPLC. Upon completion, the reaction wascooled to 5-10° C. and ethylenediamine (2.184 mL, 25.88 mmol) was added.The mixture was stirred for 1 hour, and then n-heptane (25 mL) and water(25 mL) were added. The layers were separated and the aqueous layer wasextracted twice with n-heptane (25 mL). The combined organic layers werecombined and washed with aqueous hydrogen chloride (1.0N, 25 mL), water(25 mL), saturated aqueous sodium bicarbonate (25 mL), and saturatedaqueous sodium chloride (25 mL). The solution was dried with sodiumsulfate, filtered, and partially concentrated in vacuo. The precipitateof(S)-N-(2-(4-isopropyl-4,5-dihydrooxazol-2-yl)-6-methylphenyl)methanesulfonamidewas filtered, and the cake was washed with heptane (20 mL). The filtrateand wash were concentrated to dryness, and the crude product waspurified on Biotage® Snap KP-Sil 100 g cartridge conditioned withheptane (4CV). The crude product was loaded with heptane and eluted withheptane/ethyl acetate (9:1, 4:1, 7:3, and 1:1 heptane/ethyl acetate, 5CV each). The fractions containing product were pooled to provide 28(2.773 g, 72%) as a pale yellow oil upon removal of volatiles in vacuo.

Methyl2-((2R,4aS,6S,7R,8S,8aS)-6-((1S,E)-6-((2S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)-1-((tert-butyldimethylsilyl)oxy)-4-oxohex-2-en-1-yl)-7,8-bis((tert-butyldimethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)acetate

Methyl2-((2R,4aS,6S,7R,8S,8aS)-6-((1S,E)-6-((2S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)-1-((tert-butyldimethylsilyl)oxy)-4-hydroxyhex-2-en-1-yl)-7,8-bis((tert-butyldimethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)acetate28 (2.773 g, 0.1.856 mmol) was dissolved in DCM (13.4 mL), and water(1.67 μL, 0.093 mmol) was added. Dess-Martin periodinane (0.944 g, 2.227mmol) was added in portions, while maintaining the temperature below 22°C. When the reaction was deemed complete, 25 mL saturated aqueous sodiumbicarbonate was added followed by 10% aqueous sodium thiosulfate (25mL). The mixture was stirred for 20 minutes, and the layers partitioned.The aqueous layer was extracted with dichloromethane (DCM) (2×40 mL).The combined organic layers were concentrated in vacuo to provide 29(2.688 g, 1.8 mmol, 97% yield). ¹H NMR (400 MHz, CDCl₃) δ: 7.92 (dd,2H), 7.68 (t, 1H), 7.60 (t, 2H), 7.55-7.63 (m, 2H), 7.08 (dd, 1H), 6.29(d, 1H), 5.08-5.14 (m, 1H), 4.85-4.89 (m, 1H), 4.83 (s, 1H), 4.76 (s,1H), 4.62 (d, 1H), 4.17-4.24 (m, 1H), 4.07 (s, 1H), 3.87-4.02 (m, 1H),3.83 (s, 4H), 3.65-3.66 (m, 3H), 3.65 (s, 3H), 3.62-3.69 (m, 2H),3.52-3.61 (m, 2H), 3.47 (dd, 1H), 3.41-3.42 (m, 3H), 3.41 (s, 3H),3.25-3.43 (m, 6H), 2.95-3.06 (m, 1H), 2.90 (dd, 1H), 2.44-2.73 (m, 4H),2.30-2.37 (m, 1H), 2.12-2.24 (m, 2H), 1.95-2.02 (m, 1H), 1.63-1.92 (m,6H), 1.13-1.58 (m, 5H), 1.02-1.08 (m, 3H), 1.05 (d, 3H), 0.98-1.10 (m,3H), 0.93-0.95 (m, 2H), 0.94 (s, 9H), 0.92 (s, 9H), 0.87 (s, 18H),0.89-0.85 (m, 2H), 0.85 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H), 0.08 (s,3H), 0.08 (s, 3H), 0.03 (s, 3H).

Methyl2-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-2-(2-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-dihydroxypropyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)ethyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-7-yl)acetate

Methyl2-((2R,4aS,6S,7R,8S,8aS)-6-((1S,E)-6-((2S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)-1-((tert-butyldimethylsilyl)oxy)-4-oxohex-2-en-1-yl)-7,8-bis((tert-butyldimethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)acetate29 (4.26 g, 2.854 mmol) was dissolved in THF (63.9 mL, 779.855 mmol) andN,N-dimethylacetamide (21.30 mL, 227.375 mmol). Imidazole hydrochloride(0.880 g, 8.421 mmol) was added followed by TBAF in THF (18.55 mL,18.554 mmol). The reaction was monitored by TLC (silica gel; 1:1MTBE/heptane and 9:1 EtOAc/MeOH) and stirred for 10 d. When the reactionwas deemed complete, the reaction mixture was concentrated in vacuo atRT, and the residue was dissolved in ethanol (90 mL). 1H-imidazolehydrochloride (2.510 g, 24.007 mmol) and water (42.6 mL, 2364.659 mmol)were added, and the reaction was monitored by TLC for the formation ofcompound 30. After 24 h, an additional portion of imidazolehydrochloride (2.5 g) was added, and the solution was stirred for 72 h.Aqueous saturated sodium bicarbonate was added followed by toluene, andthe mixture was concentrated in vacuo to remove EtOH. The residue wasdiluted with 30 volumes of 2:1 (v/v) THF/toluene, and the phasesseparated. The aqueous layer was extracted with 10 volumes of 1:1 (v/v)THF/toluene. The combined organic layers were washed with water (2×10volumes), dried with sodium sulfate, and concentrated in vacuo. Theresidue was purified on Biotage® with 300 g HP-Sil cartridge using 2:1toluene/acetonitrile (1 L), 1:1 toluene/acetonitrile (2 L), and 9:1acetonitrile/MeOH. Fractions containing compound 30 were pooled andconcentrated in vacuo to provide 1.8 g product. ¹H NMR (400 MHz, CDCl₃)δ 7.93 (d, 2H), 7.68 (t, 1H), 7.60 (t, 2H), 4.89 (d, 1H), 4.82 (s, 1H),4.77 (s, 1H), 4.68-4.65 (m, 2H), 4.60-4.57 (m, 1H), 4.42-4.40 (m, 1H),4.29-4.22 (m, 2H), 4.18 (dd, 1H), 4.05 (dd, 1H), 3.98-3.88 (m, 4H), 3.80(td, 2H), 3.64 (s, 3H), 3.70-3.49 (m, 1H), 3.42 (s, 3H), 3.38-3.28 (m,2H), 3.15-3.00 (m, 2H), 2.91 (dd, 1H), 2.65-2.54 (m, 3H), 2.38 (d, 1H),2.34 (d, 1H), 2.24-2.12 (m, 6H), 2.11-1.84 (m, 5H), 1.84-1.57 (m, 6H),1.56-1.45 (m, 2H), 1.44-1.26 (m, 4H), 1.09-0.97 (m, 4H).

Methyl2-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-2-(2-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)ethyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-7-yl)acetate

Methyl2-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-2-(2-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-dihydroxypropyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)ethyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-7-yl)acetate30 (0.734 g, 0.813 mmol) was dissolved in dichloromethane (DCM) (7.34mL, 114.076 mmol). 2,6-Lutidine (0.568 mL, 4.877 mmol) was added thesolution, which was then cooled to 0° C. tert-Butyldimethylsilyltrifluoromethanesulfonate (0.467 mL, 2.032 mmol) was added, and thereaction was stirred and monitored for completion by TLC. Uponcompletion of the reaction, aqueous saturated sodium bicarbonate wasadded, and the mixture was stirred for 15 minutes. The layers wereseparated, and the aqueous layer was extracted with DCM. The combinedorganic layers were washed sequentially with water, 0.1N HCl, water, andaqueous saturated sodium bicarbonate. The combined organic layers wereconcentrated in vacuo to provide a yellow oil. The product was purifiedby suction silica gel column chromatography (14 g SiO₂, 230-400 m). Thecrude reaction mixture was loaded with DCM/heptane, and the column waseluted with heptane/MTBE (1:1 (v/v), 150 mL) followed by MTBE (2×150mL). The fractions containing the product were pooled and concentratedin vacuo to provide 31 (848 mg) of white foam. ¹H NMR (400 MHz, C₆D₆)b=7.96-7.90 (m, 2H), 7.08-7.02 (m, 3H), 4.88-4.84 (m, 1H), 4.82-4.78 (m,1H), 4.76-4.71 (m, 1H), 4.66-4.62 (m, 1H), 4.52-4.42 (m, 1H), 4.39-4.29(m, 2H), 4.15-4.04 (m, 4H), 4.03-3.84 (m, 5H), 3.81-3.60 (m, 6H), 3.45(s, 3H), 3.27 (s, 3H), 3.16-3.08 (m, 1H), 2.94 (s, 2H), 2.58-2.48 (m,3H), 2.48-2.34 (m, 2H), 2.30-1.87 (m, 12H), 1.00 (s, 9H), 0.94 (s, 9H),0.96-0.90 (m, 2H), 0.93 (d, J=2.0 Hz, 1H), 0.93 (d, J=1.6 Hz, 1H),0.89-0.81 (m, 8H), 0.19 (s, 2H), 0.17 (s, 3H), 0.06 (s, 3H), 0.06 (s,3H)

Bis-TBS Ether Phenylsulfone 32

Treat methyl2-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-2-(2-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)ethyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-7-yl)acetate31 in a solvent (e.g., THF, 2-methyltetrahydrofuran, MTBE, DME, toluene,chlorobenzene, tert-butanol, isopropanol, or another solvent) (30-100volumes) with a base (e.g., potassium t-butoxide, KHMSA, potassiumpentoxide, or a similar base) (1-5 equiv.). The resulting mixture isstirred at at a temperature between −20° C. and reflux and is monitoredfor consumption of starting material. The reaction can be quenched byaddition of 0.1N HCl (10 volumes). The mixture can be extracted withMTBE or other suitable organic solvent. The organic layers can becombined and washed sequentially with water, saturated aqueous sodiumbicarbonate, and water. The resulting organic solution can be dried overNa₂SO₄, filtered, and concentrated in vacuo to provide 32. The productcan be purified by chromatography if necessary.

Bis TBS-Ether 18

Compound 32 was dissolved in THF (0.35 mL) and MeOH (0.25 mL), and thesolution was cooled to −78° C. Samarium (II) iodide (1.0 M in THF, 0.12mL, 2.5 eq) was added, and the reaction was monitored by TLC. Thereaction progressed to approximately 50% completion. Additional samarium(II) iodide was added (1.0M in THF, 0.6 mL, 12.5 eq) in portions over 1h. The reaction conversion remained at 50%. The reaction mixture wasworked up by the addition of Rochelle salt/potassium carbonate/water(1:1:10 ratio; 20 mL) and extracted with EtOAc (3×20 mL). The combinedextracts were sequentially washed with saturated sodium bicarbonate,water, and brine before drying with sodium sulfate. After filtering, thefiltrate is concentrated in vacuo to provide a residue of 18 and 32. ¹HNMR analysis against an authentic sample of 18 confirmed the structuralassignment.

OTHER EMBODIMENTS

Various modifications and variations of the described device and methodsof use of the invention will be apparent to those skilled in the artwithout departing from the scope and spirit of the invention. Althoughthe invention has been described in connection with specificembodiments, it should be understood that the invention as claimedshould not be unduly limited to such specific embodiments. Indeed,various modifications of the described modes for carrying out theinvention that are obvious to those skilled in the art are intended tobe within the scope of the invention.

Other embodiments are in the claims.

The invention claimed is:
 1. A method of preparing an intermediate inthe synthesis of eribulin, said method comprising performing amacrocyclization reaction on a non-macrocyclic intermediate, saidmacrocyclization reaction producing said intermediate in the synthesisof eribulin by forming a C.2-C.3 bond in the structure of eribulin,wherein said non-macrocyclic intermediate is a compound of formula (IIA)or a salt thereof:

wherein each R is independently optionally substituted alkyl oroptionally substituted aryl; (i) R₁is H or a hydroxyl protecting group,and R₂ and R₃ combine to form a double bond; or (ii) R₁and R₂ combine toform a bond, and R₃ is H; each P₃ is independently H or a hydroxylprotecting group, and X₂ is oxo; or both P₃ groups and X₂, together withthe atoms to which each is attached, combine to form ketal; P₄ is H or ahydroxyl protecting group; and X is O, and each of P₁ and P₂ isindependently H or a hydroxyl protecting group, or P₁ and P₂, togetherwith the atoms to which each is attached, combine to form a cyclicprotected diol; or X is N, and P₁ is H or a hydroxyl protecting group,and X and P₂ combine to form optionally masked amino; or P₁ and P₂,together with the atoms to which each is attached, combine to form anaminal or 1,3-oxazolidin-2-one-5-yl; and wherein said intermediate inthe synthesis of eribulin is a compound of formula (IIB) or a saltthereof:

and said performing said macrocyclization reaction comprises contactingsaid compound of formula (IIA) or salt thereof with an organic base anda Lewis acid.
 2. The method of claim 1, wherein each R is optionallysubstituted C₁₋₆ alkyl.
 3. The method of claim 1, wherein at least oneof P₁ and P₂ is a hydroxyl protecting group.
 4. The method of claim 1,wherein both P₃ groups and X₂, together with the atoms to which each isattached, combine to form ketal.
 5. The method of claim 1, wherein P₄ isa hydroxyl protecting group.
 6. The method of claim 1, wherein saidorganic base is DBU or triethylamine.
 7. The method of claim 1, whereinsaid Lewis acid is a salt of Li or Zn.
 8. The method of claim 1, whereinX is O.
 9. The method of claim 1, wherein X is N.
 10. The method ofclaim 9, wherein X and P₂ combine to form optionally masked amino.
 11. Amethod of preparing:

said method comprising: (A) producing a compound of formula (IIB) orsalt thereof from a compound of formula (IIA) or a salt thereof:

wherein each R is independently optionally substituted alkyl oroptionally substituted aryl; (i) R₁is H or a hydroxyl protecting group,and R₂ and R₃combine to form a double bond; or (ii) R₁ and R₂ combine toform a bond, and R₃is H; each P₃ is independently H or a hydroxylprotecting group, and X₂ is oxo; or both P₃ groups and X₂, together withthe atoms to which each is attached, combine to form ketal; P₄ is H or ahydroxyl protecting group; and X is O, and each of P₁ and P₂ isindependently H or a hydroxyl protecting group, or P₁ and P₂, togetherwith the atoms to which each is attached, combine to form a cyclicprotected diol; or X is N, and P₁ is H or a hydroxyl protecting group,and X and P₂ combine to form optionally masked amino; or P₁ and P₂,together with the atoms to which each is attached, combine to form anaminal or 1,3-oxazolidin-2-one-5-yl; and the compound of formula (IIB)having the following structure:

(B) producing a compound of formula (ID) or salt thereof from thecompound of formula (IIB) or salt thereof, the compound of formula (ID)having the following structure:

and (C) producing eribulin or eribulin mesylate from the compound offormula (ID) or salt thereof.
 12. The method of claim 11, wherein thecompound of formula (IIB) or salt thereof is produced by reacting thecompound of formula (IIA) or salt thereof with an organic base and aLewis acid.
 13. The method of claim 11, wherein producing said compoundof formula (ID) or salt thereof comprises reacting the compound offormula (IIB) or salt thereof with a hydroxyl protecting group removingagent.
 14. The method of claim 11, wherein both P₃groups and X₂,together with the atoms to which each is attached, combine to formketal.
 15. The method of claim 11, wherein, in the compound of formula(ID) or salt thereof, both P₃ groups and X₂, together with the atoms towhich each is attached, combine to form ketal.
 16. The method of claim11, wherein, in the compound of formula (ID) or salt thereof, P₁ is H.17. The method of claim 11, wherein, in the compound of formula (ID) orsalt thereof, X is O, and P₂ is H.
 18. The method of claim 17, whereinsaid producing eribulin or eribulin mesylate from the compound offormula (ID) or salt thereof comprises aminating the compound of formula(ID) or salt thereof.
 19. The method of claim 11, wherein, in thecompound of formula (ID) or salt thereof, X and P₂ combine to form amasked amino.
 20. The method of claim 19, wherein said producingeribulin or eribulin mesylate from the compound of formula (ID) or saltthereof comprises reacting the compound of formula (ID) or salt thereofwith an amino unmasking agent.
 21. The method of claim 11, whereineribulin mesylate is produced by salifying eribulin with methanesulfonicacid.
 22. A compound of formula (IIA) or (IIB):

or a salt thereof, wherein each R is independently optionallysubstituted alkyl or optionally substituted aryl; (i) R₁is H or ahydroxyl protecting group, and R₂ and R₃ combine to form a double bond;or (ii) R₁and R₂ combine to form a bond, and R₃ is H; each P₃ isindependently H or a hydroxyl protecting group, and X₂ is oxo; or bothP₃ groups and X₂, together with the atoms to which each is attached,combine to form ketal; P₄ is H or a hydroxyl protecting group; and X isO, and each of P₁ and P₂ is independently H or a hydroxyl protectinggroup, or P₁ and P₂, together with the atoms to which each is attached,combine to form a cyclic protected diol; or X is N, and P₁ is H or ahydroxyl protecting group, and X and P₂ combine to form optionallymasked amino; or P₁ and P₂, together with the atoms to which each isattached, combine to form an aminal or 1,3-oxazolidin-2-one-5-yl.